### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

D A T E: 1 5

- SE P T-20 1 5 O F F I C E O F
C H E M ICAL S A FETY AND
PO L LU TI O N P R EVE N TIO N



### SUBJEC T : P r o fe n o fo s: Human H ealt h D raft Ri sk Assess m e nt ( DRA ) for R eg i s tration

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### T O : Chr i st i na Sche lt e m a
P a tr ic i a P a rr o tt

P es t ic i de R e

- Ev alu a t io n D i v i s i o n ( PRO ) ( 7 50 8P )

Thi s d oc um e nt p ro v id es th e HED 's hum an h ea lth ri sk assess m e n t for th e Reg i s t rat i o n R ev i e w o f

pro fe n ofos ( 0

- ( 

### 4-br o m o

- 2

- c hl oro ph e n y l )

- O

- et h y l S- p ro p y l ph osp h oroth io a te ). T h e h azard

c h a r acte ri za ti o n
, e n d po i n t se l e cti o n
, an d r is k assess m e nt we r e provide d b y Mo ni q u e P e rr on (RAB l ); t h e r es i d u e ch e mi s tr y assess m e nt and di e t a r y expos u re assess m e n ts we r e p ro vi d ed b y Sara h L evy (RA B 1 ); a nd th e o ccup a ti o n a l and r es id e nti a l ex p os ur e assess m e nt was provide d by

Ke ll y Lowe (RA B I).

Pa g e I of 57Page 2 of 57 

### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ............. 4

2.0 HED Recommendations

................................ ................................ ................................ ....... 7

2.1 Data Deficiencies

................................ ................................ ................................ ............. 7

2.2 Tolerance Considerations

................................ ................................ ................................ . 7

2.2.1 Enforcement Analytical Method

................................ ................................ ............... 7

2.2.2 International Harmonization

................................ ................................ ..................... 8

2.2.3 Revisions to Established Tolerances

................................ ................................ ......... 8

2.3 Label Recommendations

................................ ................................ ................................ .. 9

3.0 Introduction

................................ ................................ ................................ .......................... 9

3.1 Chemical Identity

................................ ................................ ................................ ............. 9

3.2 Physical/Chemical Characteristics

................................ ................................ ................... 9

3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 10

3.4 Anticipated Exposure Pathways

................................ ................................ ..................... 10

3.5 Consideration of Environmental Justice

................................ ................................ ........ 11

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................ 11

4.1 Toxicology Studies Available for Analysis

................................ ................................ ... 11

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

................................ ...... 12

4.2.1 Dermal Absorption

................................ ................................ ................................ .. 13

4.3 Toxicological Effects

................................ ................................ ................................ ..... 13

4.3.1 Critical Durations of Exposure

................................ ................................ ............... 13

4.4 Literature Review on Neurodevelopment Effects

................................ .......................... 15

4.5 Safety Factor for Infants and Children (FQPA SF)

................................ ........................ 20

4.5.1 Completeness of the Toxicology Datab ase

................................ ............................. 20

4.5.2 Evidence of Neurotoxicity

................................ ................................ ...................... 20

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... 20

4.5.4 Residual Uncertainty in the Exposure Database

................................ ..................... 21

4.6 Toxicity Endpoint and Point of Departure Selections

................................ .................... 21

4.6.1 Dose

- Response Assessment

................................ ................................ .................... 21

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........ 24

4.6.3 Cancer Classification and Risk Assessment Recommendation

.............................. 24

4.6.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

................................ ................................ ................................ ............................ 24

4.7 En docrine Disruption

................................ ................................ ................................ ..... 26

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 27

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ........... 27

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............... 27

5.1.2 Summary of Environmental Degradation

................................ ............................... 28

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 28

5.1.4 Residues of Concern Summary and Rationale

................................ ........................ 29

5.2 Food Residue Profile

................................ ................................ ................................ ...... 29

5.3 Water Residue Profile

................................ ................................ ................................ .... 29

5.4 Dietary Risk Assessment

................................ ................................ ................................ 30

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ..... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 31

5.4.3 Acute Dietary Risk Assessment

................................ ................................ .............. 31Page 3 of 57 

### 5.4.4 Steady

- State Dietary Risk Assessment

................................ ................................ ... 32

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............ 34

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 34

6.1 Residential Handler Exposure

................................ ................................ ........................ 34

6.2 Post

- Application Exposure

................................ ................................ ............................. 34

7.0 Residential Bystander Post

- Application Inhalation Exposure

................................ ........... 35

8.0 Spray Drift

................................ ................................ ................................ ......................... 35

9.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 39

10.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 39

11.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 39

11.1 Short

- and Intermediate

- Term Handler Risk

................................ .............................. 39

11.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

...................... 41

11.2.2 Occupational Post

- Application Dermal Exposure/Risk Estimates

......................... 42

12.0 References

................................ ................................ ................................ ............................. 45 Appendix A. Toxicology Profile

................................ ................................ ................................ .. 47

A.1 Toxicology Data Requirements

................................ ................................ ...................... 47 Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling

................... 52 Appendix C. Summary Tables of Benchmark Dose (BMD) Analyses

................................ ....... 53 Appendix D. Physical/Chemical Properties

................................ ................................ ................. 56 Appendix E. International Residue Limits

................................ ................................ ................... 57Page 4 of 57 

### 1.0 Executive Summary

Background

Profenofos is an organophosphate (OP) insecticide

- miticide used for insect and mite control on cotton. There is only one end

- use product label registered with profenofos as the active ingredient (ai) (EPA Reg. #100

- 669; Curacron® 8E Insecticide

- Miticide). This product is formulated as an emulsifiable concentrate (EC), containing 73% ai or 8 lb ai/gallon, and is a restricted use pesticide. The product label indicates that a closed mixing/loading system and enclosed cab groundboom equipment are required. The maximum single application rate is 0.5 lb ai/A. The maximum seasonal rate is 5 lb ai/A/season, with a 5 day minimum retreatment interval (RTI).

Based on the registered use pattern for profenofos, h umans may be exposed to profenofos in food (from co ttonseed oil as well as secondary residues in milk and meat byproducts) and drinking water since profenofos may be applied directly to growing crops and application may result in profenofos reaching surface and ground water sources of drinking water. D erm al and inhalation exposures are anticipated fo r occupational handlers as well as dermal exposures for post

application workers. There are currently no registered residential uses of profenofos; however, there is the potential for non

- occupational exposure as a result of spray drift.

Hazard Assessment

Profenofos is a member of the OP class of pesticides. Like other OPs, the initiating event in the mode of action (MOA) / adverse outcome pathway (AOP) for profenofos involves inhibition of the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or periphe ral nervous system . For profenofos, AChE inhibition is the most sensitive endpoint in the toxicology database i n multiple species, durations, lifestages, and routes. Profenofos does not require metabolic activation to an oxon metabolite to inhibit AChE ( i.e., the parent compound is the active form inhibiting AChE). OPs also exhibit a phenomenon known as steady

- state AChE inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the production of new, uninhibited enzyme. Therefore, steady

- state exposure assessments of 21 days and longer were conducted instead of the traditional chronic or long

- term assessments.

The toxicology database for profenofos is considered adequate for risk assessment. There are acceptable studies available for toxicity endpoint selection. Profenofos has high

- quality dose

response data acro ss multiple lifestages, durations, and routes for both red blood cell (RBC) and

brain AChE inhibition. Dermal and inhalation studies all ow for route

- specific evaluation. Clinical signs of neurotoxicity can be found throughout the database following acute exposures at doses much higher than those causing inhibition of AChE. No ne of the submitted studies in the toxicology database for prof enofos suggest increased sensitivity to profenofos based on

AChE inhibition ; however, the Food Quality Protection Act (FQPA) Safety Factor (SF) has been

retained for infants, children, youths, and women of childbearing age for all exposure scenarios

due to uncertainty in the human dose

- response relationship for neurodevelopmental effects (s eePage 5 of 57 

### Section 4.4)

. Additionally, for inhalation exposures, a database uncertainty factor was applied for extrapolation from a lowest

- observed adverse

- effect level (LOAEL) to a no

- observed

adverse

- effect level (NOAEL) (UF L 

### ). For all exposure scenarios, interspecies (10X) and intraspecies (10X) uncertainty factors were applied . As a result, a total uncertainty factor of

1000X was applied for all exposure scenarios, except d ietary exposures for the adult population subgroup 50

- 99 years old where the FQPA SF does not apply (total uncertainty factor = 100X)

and inhalation exposures (maximum total uncertainty factor of 3000X )

.

Profenofos is classified as a “Group E Chemical

– evidence of non

- carcinogenicity for humans” based on lack of evidence of carcinogenicity in rats and mice. A quantitative cancer risk assessment is not required.

Dietary (Food and Water) Exposure and Risk

The existing residue chemistry database for profenofos is adequate for risk assessment purposes. An unrefined acute dietary exposure assessment was conducted to estimate the dietary exp osure and risk associated with Registration R eview. The acute dietary exposure assessment incorporated tolerance level residues, DEEM default processing factors, and 100% crop treated (PCT). The Environmental Fate and Effects Division (EFED) provided a surface water estimated drinking water concentrations ( EDWC ) of 5.92 ppb from the Tier 2 Surface Water

Concentratio n Calculator (SWCC) version 1.106 (EFED, 2014)

. The unrefined acute aggregate dietary (food + d rinking water) exposure estimates are below HED’s level of concern [ <100%

the acute population adjusted dose (aPAD) ] for the U.S. po pulation and all population subgroups

at the 95 th 

### percentile . Combined dietary exposure from food + drinking water is 3 8 % of the aPAD for the U.S. population and 80 % of the aPAD for children 1

- 2 years old, the highest exposed population subgroup.

The DEEM acute module was used to conduct refined two

- day (steady

- state) average assessments using the steady

- state endpoint, 2

- day average dietary exposure, and 21

- day rolling
water averages. Steady

- state assessments were conducted for drinking water alo ne, food alone, and food + drinking water. T he steady

- state dietary exposure assessments assumed , where applicable, an average field trial value for cotton, a cottonseed oil processing factor, and

tolerance

- level and processing factors for meat and milk c ommodities. The cotton PCT was applied to cotton and all meat/milk commodities; therefore, results are discussed at the 99.9 th


### percentile of exposure. However, when discussing drinking water only, results are discussed at

the 95 th 

### percentile of exposure as PCT was not applied to drinking water. EFED provided daily

time

- series outputs that simulate 29 years of residues of profenofos in drinking water for 5 cotton application scenarios (TX, MS, NC, CA cotton reservoir, and MS cotton pond). These

distribut ions were used as a residue

- distribution file (RDF) in DEEM for direct all sources and indirect all sources. For the partially

- refined food alone steady

- state assessment, children 1

- 2 years old are the highest exposed subpopulation at 350% ssPAD at the 99 .9 th 

### percentile of exposure. Four out of the five drinking water only scenarios had at least one subpopulation that

was >100% aPAD at the 95 th 

### percentile (CA cotton scenario had estimates <100% for all populations at the 95 th 

### percentile). For the partial ly

- refined food + drinking water exposure estimates at the 99.9 th 

### percentile, all five scenarios are of concern to HED (>100% ssPAD). The TX drinking water scenario had the overall highest risk estimates (all infants <1 year old (1600%Page 6 of 57 

### ssPAD)). The CA co tton scenario had the overall lowest risk estimates (children 1

- 2 years old was the highest exposed population subgroup at the 99.9 th 

### percentile at 350% ssPAD)). The other three food + drinking water scenarios were similar to (but lower than) the TX scena rio.

Residential (Non

- Occupational) Exposure and Risk There are currently no registered residential uses of profenofos; therefore, a quantitative residential handler and post

- application assessment was not conducted.

Spray Drift A quantitative non

- occupational spray drift assessment was conducted for the registered uses of profenofos. Risk estimates related to spray drift are of concern at various distances from the edge of the field for adults and children (1 to <2 years) depend ing on the spray drift scenario. For adults, the screening level scenario of a high boom and very fine to fine spray requires a

distance of over 300 feet to reach a dermal margin of exposure ( MOE ) ≥ 1000. For children, the screening level scenario also r equires a distance of over 300 feet to reach a combined (dermal and incidental oral) MOE ≥1000. Drift reduction technologies, such as using coarser sprays and lowering boom height for groundboom sprayers, reduces risk concerns; however, there are still

ri sk estimates of concern at the field edge.

Occupational Exposure and Risk Occupational handler dermal and inhalation exposure and risk estimates were calculated for the registered uses of profenofos. Dermal and inhalation risk estimates were combined i n this assessment since the toxicological effects for these exposure routes were the same. A total aggregated risk index (ARI) was used to combine dermal and inhalation risk estimates since the level of concern (LOC) values for dermal exposure (1000 ) and inhalation exposure (3000) are different. The target ARI is 1; therefore, ARIs of less than 1 are risk estimates of concern. The

oc cupational handler exposure and risk estimates indicate that the steady

- state dermal and

inhalation combined ARIs are of co ncern to HED (i.e., ARI ≤ 1) for all scenarios. Occupational
post

- application dermal exposure and risk estimates were assessed for the registered cotton use of profenofos using submitted chemical

- specific dislodgeable foliar residue (DFR) data and dislodg eable cotton boll data. Based on the current exposure assessment, post

- application risk estimates remain a concern (i.e., MOEs <1000) up to 4 days after application for hand weeding and up to 9 days after application for scouting activities . Post

- applica tion risk estimates associated with harvesting activities are a concern (MOEs <1000) 14 days after treatment, which would be the earliest harvesting could occur after application based on the current pre

- harvest interval (PHI). An additional calculation w as performed to estimate post

- application exposure

and risk using the cotton boll residue data from the day of sampling (day 44); however, there were still risk estimates of concern for all harvesting activities even 44 days after application at which poin t residue values were less than the limit of quantification (LOQ) in the study.

The current product

- label restricted entry interval (REI) is specified as 48 hours (72 hours in areas that receive less than 25 inches of rain per year). The REI on the registered label is in line with the Worker Protection Standard [40 CFR 156.208(c)(2)] assignments for ais that are classified as Toxicity Category I for acute dermal, eye irritation, or primary skin irritation, and for organophosphates in particular . How ever, there were risk estimates of concern related to all

activities associated with cotton at the current label

- prescribed REI.Page 7 of 57 

### Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessmen t was not performed for profenofos at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for profenofos.

Environmental Justice:

Pote ntial areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- In come Populations," http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf.

Human Studies Review : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical

. These data, which include studies from Pesticide Handler Exposure Database (PHED) 1.1, the Agricultural Handlers Expos ure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 4 0 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on th eir use, can be found at the Agency website 1



### .

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review eligibility of profenofos

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Profenofos is adequately recovered using the Food and Drug Administration ( FDA ) protocol multiresidue methods (MRMs) D and E (PAM Volume 1, Sections 302, 303 and 304). The plant and livestock data collection methods for profenofos were submitted to FDA as confirmatory (lettered) methods for inclusion in PAM Volume II. Independent laboratory and EPA method validation are not required for these confirmatory methods. The FDA PESTDATA database dated 1/94 (PAM Volume I, Appendix I) indicates that profenofos i s completely recovered (>80% using multiresidue method Section 302 (Luke method; Protocol D) and partially recovered (50

- 80%) using Sections 303 (Mills, Olney, Gaither method; Protocol E, nonfatty) and 304 (Mills fatty food method; Protocol E, fatty).

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pestici des/science/post

- app

- exposure

- data.htmlPage 8 of 57 

### 2.2 .2 International Harmonization

U.S. permanent tolerances are summarized in Appendix E along with International Maximum Residue Limits (MRLs) established by Codex Alimentarius Commission. Mexico adopts the U.S. tolerances and/or Codex MRLs for its export purposes. Canada has not established MRLs for profenofos. Codex has a maximum residue limit (MRL) for “cotton seed” at 3 ppm. For purposes of harmonization, HED recommends increasing the existing U.S. cotton, undelinted seed tolerance of 2.0 ppm to 3.0 ppm.

2.2.3 Revisions to Established Tolerances

Adequate field trial data have been submitted and reviewed for cotton undelinted seed and cotton gin byproducts. Field trials reflected use of the registered EC formulation at the maximum registered use patterns. Permanent tolerances are established for profenofos residues under 40 CFR §180.404 in/on cotton, undelinted seed at 2.0 ppm ; cotton gin byproducts at 55.0 ppm ; milk at 0.01 ppm; and the fat, meat, and meat byproducts of cattle, goat, horse, and sheep at 0.05 ppm.

Codex has a MRL for “cotton seed ” at 3 ppm. For purposes of harmonization, HED recommends increasing the existing U.S. cotton, undelinted seed tolerance of 2.0 ppm to 3.0

ppm.

Based on the available cottonseed processing study which demonstrated that residues of profenofos do not con centrate in cottonseed meal or oil (refined, bleached, and deodorized), and concentrate marginally (1.4 X ) in hulls, tolerances are not required for these processed

commodities.

The tolerance expression for profenofos has been reviewed and should be update d as follows based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

“Tolerances are established for residues of the insecticide profenofos, including its metabolites and degradates, in or on the commodities in the table below. Co mpliance with the tolerance levels specified below is to be determined by measuring only profenofos ( O

- (4

- bromo

- 2

- chlorophenyl)

- O

- ethyl S

- propyl phosphorothioate) in or on the

commodities:”

Table 2.2.3.1. Tolerance Summary for Profenofos.

Commodity Established Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments ( correct commodity definition )

Cattle, fat 0.05 0.05
Cattle, meat 0.05 0.05 Cattle, meat byproducts 0.05 0.05 Cotton, gin byproducts 55.0 55 Correct number of significant figures to be consistent with HED policy
Cotton, undelinted seed 2.0 3.0 Increase in tolerance level for purposes

of harmonization.
Goat, fat 0.05 0.05
Goat, meat 0.05 0.05 Goat, meat byproducts 0.05 0.05Page 9 of 57 Horse, fat 0.05 0.05
Horse, meat 0.05 0.05 Horse, meat byproducts 0.05 0.05

Milk 0.01 0.01 Sheep, fat 0.05 0.05 Sheep, meat 0.05 0.05 Sheep, meat byproducts 0.05 0.05



### 2.3 Label Recommendations

No label recommendations have been identified. Curre nt t ol e r a n ce s n ee d to be up d a ted a s discus s e d in Section 2.2.3

. A summary of the risk estimates has been provided, and shows that

there are risk estimates of concern for registered uses of profenofos based on the use information,

label

- required personal protective equipment ( PPE; i.e., engi neering controls)

, and REIs.

3.0 Introduction

3.1 Chemical Identity

Table 3.1 .1 . Test Compound Nomenclature. Compound

Common Name Profenofos

Chemical Class Organophosphate, OP

Molecular Formula C 11 H 15 BrClO 3 PS Molecular Weight 373.65 g/mole

IUPAC Name ( RS )

- ( O

- 4

- bromo

- 2

- chlorophenyl O

- ethyl S

- propyl phosphorothioate)

CAS Name O

- (4

- bromo

- 2

- chlorophenyl) O

- ethyl S

- propyl phosphorothioate CAS Registry Number 41198

- 08

- 7

PC Code 111401



### 3.2 Physical/Chemical Characteristics

Technical profenofos is a pale yellow liquid with a boiling point of 100 ° C (1.8 Pa) and a density of 1.46 g/cm 3 

### at 20 ° C. Its molecular weight is 373.65 g/Mole. Pure profenofos is an amber

colored oily liquid with a boiling point of 110 ° C (0.001 mm Hg). Profenofos has limited solubility in water (20 ppm), but is soluble in organic solvents ( acetone, ethanol, toluene, n

octanol, and n

- hexane) at 25 ° C. It has a log octanol

- water partition coefficient of 4.83. Profenofos is stable under neutral and slightly acidic conditions, and is unstable under alkaline conditions. It has a low vapor pressure (9.001 x 10

- 7 

### mm Hg )

. A summary of physical/chemical properties for profenofos can be found in Appendix D.Page 10 of 57 

### 3.3 Pesticide Use Pattern

There is only one end

- use product la bel registered with profenofos as the ai (EPA Reg. #100

- 669; Curacron® 8E Insecticide

- Miticide). This product is formulated as an EC, containing 73% ai or 8 lb ai/gallon, and is a restricted use pesticide. The product label indicates that a closed mixing /loading system and enclosed cab groundboom equipment are required. The maximum single application rate is 0.5 lb ai/A. The maximum seasonal rate is 5 lb ai/A/season, with a 5 day minimum RTI.

The Curacron® 8E product label indicates that a closed mix ing/loading system and enclosed cab are required. Mixer, loaders, applicators, and other handlers using a closed system must also wear long sleeved shirt, long pants, shoes plus socks, chemical

- resistant gloves, chemical

resistant apron (for mixing and lo ading ), and protective eyewear. The label recommends a REI of 48 hours (72 hours in areas where rainfall is less than 25 inches per year).

Table 3.3.1 . Summary of Registered Use Directions for Profenofos.

Application Timing, Type,

and Equip. Formulation [EPA Reg. No.] Maximum Application

Rate Max No. Applications per Season Max Seasonal Application

Rate Use Directions and Limitations

Cotton

Enclosed cab

Groundboom

Make 1 st application when pest populations

reach

economic

thresholds Emulsifiable

Concentrate

100

- 669

73%ai 8 lb ai/gal

Curacron® 8E

Insecticide

Miticide 0.5 pt product/A

0.5 lb ai/A Based on max single rate and

max seasonal rate, up to 10 applications per season (not

specified on label). 5 pt/A/season

5 lb

ai/A/season • Restricted Use Pesticide

.

• Closed system mixing and loading and enclosed tractor cab required

.

• REI = 48 hours (72 hours in

areas that receive 25 inches or less of rain)

.

• Do not apply by aerial or chemigation application

.

• Loaders/mixers not allowed to

handl er more than 10 gallons/day

.

• Hand harvesting is prohibited

.

• Repeat applications at 5

- 7 days intervals as needed

.

• Apply in minimum of 5 gallons/A

.

• PHI = 14 days when diluted with water; 30 days when

diluted with oi l.

• PBI = 30 days

. REI = restricted

- entry interval, PHI= pre

- harvest interval, PBI = plant back interval



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to profenofos in food and drinking water since profenofos may be applied directly to growing crops and application may result in profenofos reaching surface and ground water sources of drinking water. There are no residential uses of profenofos ; however, there is the potential for short

- term non

- occupational exposure (dermal and incidental oral ) as a result of spray drift. Based o n the registered use pattern for profenofos , dermal and inhalation exposures are anticipated for occupational handlers and pos t

- application workers.Page 11 of 57 

### 3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the ex tent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resourc es/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pestici de exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting

. Extensive data on food consumption patterns are compiled by the USDA under th e National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Addit ionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant

. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and asso ciated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated

. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Profenofos is a member of the OP class of pesticides. Like other OPs, the initiating event in the

MOA /AOP for profenofos involves inhibition of the enzyme AChE via phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to accumulation of

ace tylcholine and ultimately to neurotoxicity in the central and/or peripheral nervous system (see Figure 1). For profenofos, AChE inhibition is the most sensitive endpoint in the toxicology database in multiple species, durations, lifestages, and routes. A ChE inhibition is the focus of this hazard characterization; the availability of reliable AChE inhibition dose response data is one of the key determinants in evaluating the toxicology database.

Figure 1. AOP for OPs.

4.1 Toxicology Studies Available for Analysis

The toxicology database for profenofos is complete for risk assessment. The acceptable profenofos studies available for risk assessment include: 

## Target
Tissue

Dose Phosphorylation
of the active site
of AChE Neurotoxicity Accumulation
of acetylcholinePage 12 of 57 

### • subchronic oral toxicity studies in rats and dogs ;

• chronic oral toxicity studies in rats and dogs ;

• carcinoge nicity studies in rats and mice ;

• developmental studies in rats and rabbits ;

• multigenerational reproduction toxicity study in rats ;

• acute and subchronic neurotoxicity studies in rats ;

• acute and repeated comparative cholinesterase assays (CCA) in juvenile and adult

rats ;

• acute delayed neurotoxicity study in hens ;

• subchronic dermal toxicity study in rabbits ;

• subchronic inhalation toxicity study in rats ;

• mutagenicity and genotoxicity studies ;

• metabolism studies in rats and monkeys ;

• immunotoxicity study in mice ;

• developmental neurotoxicity (DNT) study with AChE measurements in non

pregnant females, pregnant females, fetuses, and juvenile rats

.

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Some OPs require metabolic activation to the oxon metabolite; however, for profenofos

, the
parent compound is responsible for AChE inhibition activity (see chemical structure in Table

3.1 .1 ). Generally, absorption and distribution are rapid with extensive metabolism and no

accumulation in the tissues for OPs.

In a rat metabolism study (MRID 42334301), recovery of radioactivity for combined fecal and urine samples ranged from 97

- 108% of the administered dose, with >97% of the radioactivity

excreted in th e urine within 48 hours. Less than 0.2% of the radioactivity was expired as volatiles. Insignificant amounts of radioactivity were retained in tissues after 7 days post

exposure. Analysis of fecal material indicated that <4% of the parent compound or it s metabolites remain unabsorbed or are excreted via the biliary system into the intestinal tract. Profenofos appears to be metabolized by hydrolysis of its thiophosphate ester followed by dephosphorylation to form 4

- br omo

- 2

- chlorophenol (CGA

- 55960), which undergoes sulfate or glucuronide conjugation. Metabolites were identified as unconjugated 4

- brom o

- 2

- chlorophenol (CGA

- 55960), O

- ethyl

- O

- (2

- chloro

- 4

- bromo

- phenyl)

- phosphate ( CGA

- 47196 ) , and thiophosphoric acid O

- (4

- bromo

- 2

- chloro

- phenyl) ester O ́

- ethyl ester ( CGA

- 65867 ) . There were no apparent dose or sex

- related differences in the absorption, distribution, metabolism, or excretion of profenofos.

In a metabolism/pharmacokinetic study with rhesus monkeys, young adult males were administered a single ora l dose via capsule at 2.4 mg/animal (approximately 0.5 mg/kg). The

test material wa s rapidly absorbed with significant concentrations measured in the blood and plasma by the first blood measurement (30 minutes post

- dose). The time to reach maximum

concen tration in the blood (T
max 

### ) was reached by 1 hour post

- dose and rapidly declined

the reafter. The terminal phase elimination half

- life (t 1/2 

### ) was estimated to be 4 hours in this study. Approximately 68% of the administered dose was recovered in the excret a (urine, feces, and cage wash after 168 hours) with the majority recovered in the urine (49%). Excretion wasPage 13 of 57 

### nearly complete by 24 hours following treatment. CGA

- 55163 was identified as the major urinary metabolite, which is the glucuronide conjugate of the phenol analog (CGA

- 55960).

4.2.1 Dermal Absorption

There are no dermal penetration studies available for profenofos; however, a dermal absorption

factor is not needed because a route

- specific dermal toxicity study was used to assess dermal

exposure scenarios (see Section 4.5).

4.3 Toxicological Effects

Profenofos has high

- quality dose

- response data across multiple lifestages, durations, and routes

for both RBC and brain AChE inhibition. In the case of profenofos, RBC AChE inhibition was

more sensi tive than brain AChE inhibition and provides the basis for human health risk extrapolations. Using AChE inhibition as the critical endpoint for risk assessment protects for other cholinergic effects, such as clinical signs, which are seen at doses much higher than those causing inhibition of AChE. Clinical signs indicative of neurotoxicity seen following a single oral dose included compulsive licking, abnormal gait, salivation, lacrimation, impaired respiration, ataxia, impaired reflexes, tre mors, and decreased arousal, rearing, and motor activity

. In general, t hese clinical signs of toxicity were observed at doses approximately 100

- 200X higher than the AChE inhibition used as the basis for the acute oral p oint of departure (POD ).

There were no clinical signs noted in repeated exposure studies; however, body weight

dec rements were noted in several s tudies.

Many of the studies have been evaluated using benchmark dose (BMD) modeling techniques. Based on BMD modeling results ( M. Perron; 15

- S EP

- 2015 ; TXR # 0057250 and Appendix C),

RBC AChE inhibition is remarkably similar across oral studies for adult rats . Available studies with adult animals show similar findings in gavage and dietary studies. Studies via the dermal

and inhalation routes al low for route

- specific evaluation ; however, data from these route

- specific studies were not amenable to BMD modeling (see Section 4.5.1)

. In acute and repeated studies, AChE inhibition in juvenile rats was seen at or above dose levels eliciting inhibition in adults. In

the DNT studies, the adults were found to have considerable AChE inhibition at relatively low doses, while little or no inhibition was seen in fetuses and young juvenile rats except at the highest doses tested. As a result , no dose respons e was observed and BMD estimates were not

calculated . Pregnant females were also not found to be more sensitive than non

- pregnant
females.

Profenofos is classified as acutely toxic via the oral (Toxicity Category II) and dermal routes (Toxicity Category I or II) and classified as having low acute toxicity via the inhalation route (Toxicity Category IV). It was found to be a minimal eye irritant and moderate dermal irritant (Toxicity Category III). It was also found to be a dermal sensitizer.

4.3.1 Crit ical Durations of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. One advantage of an AOP understanding is that humanPage 14 of 57 

### health risk assessments can be refined to focus on the most relevant durations of exposure. The following text provides an analysis of the temporal pattern of AChE inhibition from acute (single) and repeated dosing studies in laboratory animals for profenofos. This analysis provides

the basis f or determining which exposure durations are appropriate for assessing human health risk. Table 4.3.1.1 provides a summary of the selected results from experimental toxicology studies with profenofos.

Table 4.3.1.1. Profenofos BMD 10 and BMDL 10 Results (mg/kg/day) for RBC AChE Inhibition Over Time

in Adult Rats.

Days of Dosing Males Females

BMD 10 BMDL 10 BMD 10 BMDL 10

1 a 13.49 11.24 3.17 1.99

10 b NMF NMF 0.38 0.17

35 c NA NA 0.32 0.19

90 d 0.33 0.29 0.66 0.54

91 e 0.14 0.12 0.13 0.12

364 e 0.17 0.15 0.22 0.18

BMD 10 = estimated dose where AChE is inhibited by 10% compared to background

. BMDL 10 = lower confidence bound on the BMD 10

. NMF = no model fit. NA = not applicable.

a MRID 46025406

– acute CCA study in rats(gavage).

b MRID 46025403

– repeat CCA study in rats (gavage).

c MRID 46025401

– DNT study in rats (dietary).

d MRID 00105255

– subchronic oral toxicity study in rats (dietary).

e MRID 00081685

– combined chronic/carcinogenicity study in rats (dietary)

– interim (91 d ays) and terminal measurements (364 days).



### As shown in Table 4.3.1.1, the acute BMD values are the largest in the table, whereas BMD values from repeated dosing exposures are remarkably similar. OPs exhibit a phenomenon known as steady

- state AChE inhibit ion. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the production of new, uninhibited enzyme. At this point, the amount of AChE inhibition at a given dose remains consistent across duration . In

genera l, OPs reach steady

- state within 2

- 3 weeks, but this can vary among OPs. In the case of profenofos, the results in Table 4.3.1.1 show a clear patte rn of steady

- state reached by 10 days of exposure. In addition to the consistency across durations, the dat a across multiple studies in rats are similar. Given the results in Table 4.3.1.1 (and Appendix C) for profenofos, acute (single

day) and steady

- state durations are appropriate for human health risk assessment. As such, the endpoint selection discussed b elow focuses on acute (single

- day) effects and steady

- state effects.

Although there are data at a shorter time period than 21 days (i.e., 10 days), exposure assessments of 21 days and longer will be conducted for all routes of exposure (i.e., oral, de rmal and inhalation) for all single chemical OP assessments. Although the durations of the toxicity and exposure assessments may differ, an exact match is not necessary and would suggest a level of precision that the toxicity data do not support. Given t his, the 21

- day and longer exposure assessment is scientifically supportable and also provides consistency with the OP cumulative risk assessment (OP Cumulative Risk Assessment ( CRA ) ; 2002, 2006) and across the single

chemical risk assessment for the OPs.Page 15 of 57 

### 4.4 Literature Review on Neurodevelopment Effects

For the OPs, historically the Agency has used inhibition of AChE as the POD for human health risk assessment; at present time, this policy continues. This science policy is based on decades

of work which shows that AChE inhibition is the initial event in the pathway to acute cholinergic neurotoxicity. The use of AChE inhibition data for deriving PODs was supported by the FIFRA SAP (2008, 2012) for chlorpyrifos as the most robust source of dose

- response data for extrapolating risk and is the source of data for PODs for profenofos . A detailed review of the epidemiological studies used in this review can be found either in the 2014 chlorpyrifos revised

draft human health risk assessment ( D. Drew; 29

- DEC

- 2014; D424485 ) or in the 2015 literature

review for oth er organophosphates ( OPP/USEPA; 15

- SEP

- 2015; D331251 ).

Newer lines of research on OPs in the areas of potential AOPs, in vivo animal studies, and notably epidemiological studies in mothers and children, have raised some uncertainty about the agency’s ri sk assessment approach with regard to the potential for neurodevelopmental effects in fetuses and children. Many of these studies have been the subject of review by the agency over the last several years as part of efforts to develop a risk assessment for chlorpyrifos ( D. Drew;

29

- DEC

- 2014; D424485 ). Initially, t he agency focused on studies from three US cohorts: 1) The Mothers and Newborn Study of North Manhattan and South Bronx performed by the Columbia Children’s Center for Environmental Health (CCCEH ) at Columbia University; 2) the

Mt. Sinai Inner

- City Toxicants, Child Growth and Development Study or the “Mt. Sinai Child Growth and Development Study;” and 3) the Center for Health Assessment of Mothers and Children of Salinas Valley (CHAMACOS) conducte d by researchers at University of California Berkeley. The agency has evaluated these studies and sought external peer review (FIFRA SAP reviews in 2008 and 2012; federal panel, 2013 2 

### ) and concludes they are of high quality. In the

three US epidemiology c ohort studies, mother

- infant pairs were recruited for the purpose of studying the potential health effects of environmental exposures during pregnancy on subsequent child development. Each of these cohorts evaluated the association between prenatal chlorpy rifos and/or OP exposure (with adverse neurodevelopmental outcomes in children through age 7

years ) . For the 2014 chlorpyrifos revised human health risk assessment ( D. Drew; 29

- DEC

2014; D424485 ) , EPA included epidemiologic research results from these thr ee US prospective birth cohort studies but primarily focused on the results of CCCEH since this cohort has published studies on the association between cord blood levels of chlorpyrifos and neurodevelopmental outcomes. The agency retained the FQPA 10X Safe ty Factor (SF) in the 2014 chlorpyrifos revised risk assessment, in large part, based on the findings of these studies.

In the 2015 updated literature review ( OPP/USEPA; 15

- SEP

- 2015; D331251 ), the agency conducted a systematic review expanding the scope o f the 2012/2014 review focused on US cohort studies with particular emphasis on chlorpyrifos. The expanded 2015 review includes consideration of the epidemiological data on any OP pesticide, study designs beyond prospective cohort studies, and non

- U.S. based studies. The updated literature review identified seven studies

which were relevant (Bouchard et al., 2010; Fortenberry et al., 2014; Furlong et al., 2014; Guodong et al., 2012; Oulhote and Bouchard , 2013; Zha ng et al., 2014; Shelton et al., 2014).

These seven studies have been evaluated in context with studies from the 2012/2014 review ( D. Drew; 29

- DEC

- 2014; D424485 ). Only a brief summary is provided below.

2 http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2008

- 0850

- 0170Page 16 of 57 

### The OP exposure being assessed in many of these studies used concentrations of urinary dialkyl phosphate metabolites (DAPs) as the urinary biomarker. Total DAPs is a non

- specific measure of OP exposure and is the sum of six separate molecules

- three dime thyl alkylphosphate (DMAP) molecules of DMP, DMTP, DMDTP, and three diethyl alkylphosphate (DEAP) molecules of DEP, DETP, and DEDTP. Each metabolite is a breakdown product from multiple OPs ( Table 4.4. 1; CDC, 2008) 3 

### . Specifically, DMP, DMTP, and DMDTP ar e associated with 18, 13, and 5 OPs, whereas DEP, DETP, and DEDTP are associated with 10, 10, and 4 OPs, respectively. Thus, using urinary DAPs alone as an exposure measure, it is not possible to separate the exposure and associated effects for single, sp ecific OPs.

Table 4.4.1.CDC Table of organophosphate pesticides and their dialkyl phosphate metabolites (2008).

Pesticide DMP DMTP DMDTP DEP DETP DEDTP

Azinphos methyl X X X
Chlorethoxyphos X X Chlorpyrifos X X Chlorpyrifos methyl X X Coumaphos X X Dichlorvos (DDVP) X

Diazinon X X Dicrotophos X

Dimethoate X X X

Disulfoton X X X

Ethion X X X

Fenitrothion X X

Fenthion X X Isazaphos

- methyl X X

Malathion X X X

Methidathion X X X Methyl parathion X X

Naled X Oxydemeton

- methyl X X

Parathion X X

Phorate X X X

Phosmet X X X Pirimiphos

- methyl X X Sulfotepp X X Temephos X X

Terbufos X X X Tetrachlorviphos X

Trichlorfon X

DMP = dimethylphosphate; DEP = diethylphosphate; DMTP = dimethylthiophosphate; DMDTP = dimethyldithiophosphate; DETP = diethylthiophosphate; DEDTP = diethyldithiophosphate.

3 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdfPage 17 of 57 

### For studies which measured urinary 3,5,6

- trichloro

- 2

- pyridinol ( TCPy) (e.g., Fortenberr y et al

. , 2014; Eskenazi et al

. , 2007; Whyatt et al

. , 2009), this metabolite can be derived from chlorpyrifos, chlorpyrifos

- methyl, and the herbicide triclopyr. TCPy is also the primary environmental degradate of chlorpyrifos, chlorpyrifos

- methyl, and tri clopyr; thus exposure can be found directly on food treated with these pesticides. CCCEH studies have largely used chlorpyrifos measured in cord blood as the specific biomarker (e.g., Lovasi et al

. , 2010; Whyatt

et al

. , 2004; Rauh et al

. , 2011). The CHAR GE study (Shelton et al, 2015) did not measure biomarkers but instead used geospatial analysis to focus on the residential proximity to OP exposure using data from the California Department of Pesticide Regulation, with five OPs accounting for a total of 7 3% of the pesticide applied near residential settings (chlorpyrifos, acephate, diazinon, bensulide, and dimethoate).

Similarly, DAPs can be found directly on food following OP applications (Zhang et al, 2008; Chen et al, 2012). Specifically, studies ha ve shown that DAPs may form as environmental degradates from abiotic hydrolysis, photolysis, and plant metabolism (Zhang et al, 2008; Chen et al, 2012; Racke et al, 1994). Furthermore, since these DAPs are excreted more rapidly and extensively than the pa rent OPs (Zhang et al, 2008; Forsberg et al, 2008), direct exposure to DAPs may lead to an overestimate of OP exposure when using urinary DAPs as a biomarker of OP exposure. The agency recognizes that this is a source of uncertainty when using DAPs for

as sessing OP exposure and will continue to monitor this issue in future assessments.

With respect to neurological effects near birth, the CHAMACOS and Mt. Sinai cohorts measured neurological effects at birth, and observed a putative association with total DEAP, total DMAP, and total DAP exposure (Engel et al., 2007; Young et al., 2005) . Similarly, a Chinese study (Zhang et al., 2014) repo rted statistically significant associations between total DEAPs, total DMAPs, and total DAPs from prenatal OP pesticide exposure and neonatal neurodevelopment assessed 3 days after birth. However, another cross

- sectional Chinese study, Guodong et al (2012 ), observed no association with urinary DAPs and a developmental quotient score for 23

- 25

month old children.

The 3 US cohorts (CCCEH, Mt. Sinai, CHAMACOS) each reported evidence of impaired mental and psychomotor development, albeit not consistent by age at time of testing (ranging from 6 month to 36 months across the three cohorts). Attentional problems and ADHD were reported by three prospective cohorts [Rauh et al, 2006; Eskenazi et al., 2007; Marks et al, 2010 ; and Fortenberry et al (2014)] investiga tors with additional support from a case control study, Bouchard et al. (2010). The exposure metric varied among these studies. Specifically, Fortenberry et al (2014) found suggestive evidence of an association with TCPy and ADHD in boys whereas statisti cally significant associations were observed by Rauh et al (2006) with chlorpyrifos exposure and ADHD

. Eskenazi et al (2007) reported associat ions with total DMAPs and total DAPs and ADHD; Marks et al (2010) reported associations with total DEAP, DMAP, an d total DAP exposure and ADHD. In a national cross

- sectional study of Canadian

children , using 2007

- 2009 data for children age 6

- 11 years (Oulhote and Bouchard , 2013), there were no overall statistically significant associations observed between child uri nary DEAP, DMAP, or total DAP metabolite levels and parentally reported behavioral problems. In contrast, Bouchard et al. (2010), looking at U.S. children age 8

- 15 years in the 2000

- 2004 National Health and Nutrition Examination Survey (NHANES), observed a positive association betweenPage 18 of 57 

### attention and behavior problems and total DAPs and DMAPs, but not DEAPs. As part of their analysis, Oulhote and Bouchard (2013) noted that their outcome assessment for behavioral problems may not have been as sensitive as Bo uchard et al (2010), which may in part account for

the difference in the observed results from these studies.

In addition, the three US cohorts and the CHARGE study have reported suggestive or positive associations between OP exposure and autism spectru m disorders (Rauh et al., 2006; Shelton et al., 2014; Eskenazi et al, 2007; Furlong et al., 2014). Specifically, Furlong et al (2014) documented suggestive evidence of an association between total DEAP exposure and reciprocal social responsiveness among b lacks and boys. Eskenazi et al (2007) reported a statistically significant association between pervasive developmental disorder (PDD) and total DAP exposure, whereas Eskenazi et al (2010) reported non

- significant, but suggestive, increased odds

of PDD of 2.0 (0.8 to 5.1; p=0.14). Rauh et al (2006) documented a significant association between PDD and specifically chlorpyrifos exposure. Both PDD and reciprocal social responsiveness are related to the autism spectrum disorder. Using a different exposure

as sessment method (geospatial analysis and residential proximity to total OP exposure), Shelton et al (2014) also showed statistically significant associations between total OP exposure and ASD. While these studies vary in the magnitude of the overall stren gth of association, they have consistently observed a positive association between OP exposure and ASD. Finally, CCCEH, Mt. Sinai, CHAMACOS have reported an inverse relation between the respective prenatal measures of chlorpyrifos and intelligence measu re s at age 7 years (Rauh et al.

, 2011; Engel et al., 2011; Bouch ard et al., 2011 )

.

Across the epidemiology database of studies, the maternal urine, cord blood, and other (meconium) measures provide evidence that exposure did occur to the fetus during gestation but the actual level of such exposure during the critical window(s) of susceptibility is not known. While significant uncertainties remain about the actual exposure levels experienced by mothers and infant participants in the children’s health cohorts, it is unlikely that these exposures resulted

in ACh E inhibition. As part of the CHAMACOS study, Eskenazi et al. (2004) measured AChE activity and showed that no differences in AChE activity were observed. The biomarker data (chlorpyrifos) from the Columbia University studies are supported by the agency’s dose reconstruction analysis using the PBPK

- PD model ( D. Drew; 29

- DEC

- 2014; D424485 )

. Following the recommendation of the FIFRA SAP (2012), the agency conducted a dose reconstruction analysis of residential uses available prior to 2000 for pregnant women and young

children inside the home. The PBPK

- PD model results indicate for the highest exposure considered (i.e., indoor broadcast use of a 1% chlorpyrifos formulation) <1% RBC AChE inhibition was produced in pregnant women. While uncertainty exists as to actual OP exposure at (unknown) critical windows of exposure, EPA believes it is unlikely individuals in the epidemiology studies experienced RBC AChE inhibition.

A review of the scientific literature on potential modes of action/adverse outcome pathwa ys (MOA/AOP) 4 

### leading to effects on the developing brain was conducted for the 2012 FIFRA SAP meeting (USEPA, 2012) and updated for the December 2014 chlorpyrifos revised risk assessment ( D. Drew; 29

- DEC

- 2014; D424485 ). In short, multiple biologically pla usible

4 Mode of action (MOA) and adverse outcome pathways (AOPs) describe a set of measureable key events that make up the biological processes leading to an adverse outcome and the causal linkages between such events.Page 19 of 57 

### hypotheses and pathways are being pursued by researchers that include targets other than AChE inhibition, including cholinergic and non

- cholinergic systems, signaling pathways, proteins, and others. However, no one pathway has sufficient data to be considered more credible than the

others. The fact that there are, however, sparse AOP data to support the in vitro to in vivo extrapolation, or the extrapolation from biological perturbation to adverse consequence significantly limits their quantitative use in risk assessment. The SAP concurred with the agency in 2008 and 2012 about the lack of definable key events in a MOA/AOP leading to developmental neurobehavioral effects. However, since the 2014 literature review, there are no substantive changes in the ability to define and quantitate steps in an MOA/AOP leading from exposure to effects on the developing brain. Published and submitted guideline DNT laboratory animal studies have been reviewed for OPs as part of the 2012/2014 review ( D. Drew; 29

- D EC

2014; D424485 ) and the updated 2015 review ( OPP/USEPA; 15

- SEP

- 2015; D331251 ). Neurobehavioral alterations in laboratory animals were often reported, albeit at AChE inhibiting doses, but there was generally a lack of consistency in terms of pattern, tim ing, or dose

- response for these effects, and a number of studies were of lower quality. However, this information does provide evidence of long

- lasting neurodevelopmental disorders in rats and mice following gestational exposure.

At this time, a MOA(s)/A OP(s) has/have not been established for neurodevelopmental outcomes. This growing body of literature does demonstrate, however, that OPs are biologically active on a number of processes that affect the developing brain. Moreover, there is a large body of in vivo laboratory studies which show long

- term behavioral effects from early life exposure, albeit at doses which cause AChE inhibition. EPA considers the results of the toxicological studies relevant to the human population, as qualitatively supported by the results of epidemiology studies. The agency acknowledges the lack of established MOA/AOP pathway and uncertainties associated lack of ability to make strong causal linkages and unknown window(s) of susceptibility. These uncertainties do not undermi ne or reduce the confidence in the findings of the epidemiology studies. The epidemiology studies reviewed in the 2012/2014 and 2015 literature reviews represent different investigators, locations, points in time, exposure assessment procedures, and outco me measurements. Despite all these differences in study design, with the exception of two negative studies in the 2015 literature review (Guodong et al, 2012; Oulhote

and Bouchard , 2013), authors have identified associations with neurodevelopmental outcom es associated with OP exposure across four cohorts and twelve study citations. Specifically, there is evidence of delays in mental development in infants (24

- 36 months), attention problems and autism spectrum disorder in early childhood, and intelligence d ecrements in school age children who were exposed to OPs during gestation. Investigators reported strong measures of statistical association across several of these evaluations (odds ratios 2

- 4 fold increased in some instances),

and observed evidence of ex posures

- response trends in some instances, e.g. , intelligence

measures.

As section 408(b)(2)(C) of the FFDCA instructs EPA, in making its “reasonable certainty of no harm” finding, that in “the case of threshold effects, an additional tenfold margin of sa fety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children

to take into account potential pre

- and postnatal toxicity and completeness of data with respect to exposure and toxicity to infants and children .” Section 408 (b)(2)(C) further states that “the Administrator may use a different margin of safety for the pesticide chemical residue only if, onPage 2 0 of 57 

### the basis of reliable data, such margin will be safe for infants and children.” Given the totality of the evidence, there is sufficient uncertainty in the human dose

- response relationship for neurodevelopmental effects which prevents the agency from reducing or removing the statutory 10X FQPA Safety Factor. For the profenofos DRA, a value of 10X has be en applied. Similarly, a database uncertainty factor of 10X will be retained for occupational risk assessments. The agency will continue to evaluate the epidemiology studies and pursue approaches for quantitative

or semi

- quantitative comparisons between doses which elicit AChE inhibition and those which are associated with neurodevelopmental outcomes prior to a revised human health risk

assessment.

4.5 Safety Factor for Infants and Children (FQPA SF)

As noted above, the lack of an established MOA/AOP makes quantitative use of the epidemiology studies in risk assessment challenging, particularly with respect to determining

dose

- response, critical duration of exposure, and window(s) of susceptibility. However, exposure levels in the range measured in t he epidemiology studies are likely low enough that they are unlikely to result in AChE inhibition. Epidemiology studies consistently identified associations with neurodevelopmental outcomes associated with OP exposure such as delays in mental development in infants (24

- 36 months), attention problems and autism spectrum disorder in early childhood, and intelligence decrements in school age children. Therefore, there is a need to protect children from exposures that may cause these effects; this need preve nts the agency from reducing or removing the statutory FQPA Safety Factor. Thus, the FQPA 10X Safety

Factor will be retained for profenofos for the population subgroups that include infants, children, youths, and women of childbearing age for all exposure scenarios.

4. 5 .1 Completeness of the Toxicology Database

The existing toxicological database is complete and adequate for characterizing profenofos toxicity. Available profenofos studies for FQPA evaluation include developmental studies in the

rat an d rabbit, reproductive toxicity studies, comparative cholinesterase studies, and neurotoxicity studies (acute, subchronic, and developmental).

As discussed in Section 4.4, there is uncertainty in the human dose

- response relationship for neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the population subgroups that include infants, children, youths, and women of childbearing age for all exposure scenarios.

4. 5 .2 Evidence of Neurotoxicity

Profenofos is an OP with an esta blished neurotoxic AOP. Neurotoxicity is the most sensitive effect in all species, routes, and lifestages and is being used in deriving the PODs.

4. 5 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of in creased quantitative or qualitative sensitivity/susceptibility to offspring following exposure to profenofos in submitted studies

.Page 21 of 57 

### As discussed in Section 4.4, there is uncertainty in the human dose

- response relationship for neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the population subgroups that include infants, children, youths, and women of childbearing age for all exposure scenarios.

4. 5 .4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to the exposure databases

. The acute dietary assessment incorporated tolerance level residues, default processing factors and 100 PCT. Although data were used to partially refine the steady

- state dietary ex posure assessments, the assessments are not expected to underestimate dietary (food and water) exposures.

4. 6 Toxicity Endpoint and Point of Departure Selections

4. 6 .1 Dose

- Response Assessment

Table 4.5.4.1 summarizes the profenofos toxicity endpoints and PODs selected from an evaluation of the database. This endpoint selection was based on a weight of the evidence evaluation using the following considerations:

• Relative sensitivity of the brain and RBC compartments : For profenofos, across most

studi es, durations, lifestages, and routes, RBC is similarly or more sensitive than the brain. As such, OPP has utilized the RBC data in POD derivation.

• Potentially susceptible populations (fetuses, juveniles, pregnancy ): The available AChE

data across multiple lifestages (adults, pregnant adults, fetuses, juveniles) show no quantitative lifestage sensitivity for profenofos. After single dose exposures, females were more sensitive than males based on RBC AChE inhibition. Consequently, data

from females were used as the basis for POD derivation for acute dietary exposures

.

• Route of exposure: It is preferred to match, to the degree possible, the route of exposure in the toxicity study with that of the exposure scenario(s) of interest. There are oral,

de rmal, and inhalation studies with profenofos which contain high

- quality dose

- response AChE data for endpoint selection.

• Duration of exposure: It is preferred to match, to the degree possible, the duration of toxicity study with that of the exposure durati on of interest. There are single day and steady

- state oral studies, but only steady

- state dermal and inhalation studies are available

.

• Consistency across studies: In cases where multiple datasets are available for a single duration, it is important to evaluate the extent to which data are consistent (or not) across studies. The profenofos database has striking consistency across studies, which allows the PODs to be derived from multiple critical studies, thereby increasing the confidence

in such values

.

Summary tables of BMD analyses can be found in Appendix C and the technical details of the analysis can be found in the BMD analysis memo ( M. Perron; 15

- SEP

- 2015 ; TXR # 0057250 ).Page 22 of 57 

### Consistent with risk assessments for other AChE

- inhibiting compounds, O PP has used a benchmark response (BMR) level of 10% and has thus calculated BMD 10 

### and BMDL 10 

### values (See Appendix B for summary of OPP’s ChE policy). The BMD 10 

### is the estimated dose where AChE is inhibited by 10% compared to background. The BMDL 10 

### is the lower confidence

bound on the BMD 10 

### . As a matter of science policy, the Agency uses the BMDL, not the BMD, for use as the POD (USEPA, 2012). All BMD/BMDL modeling for all individual datasets was completed using USEPA BMD Software to fit an exponential m odel to the data. BMD results from the OP CRA (2002, 2006) were included in the endpoint selection weight

- of

- evidence

evaluation.

Acute Dietary (all populations)

A POD for the acute dietary (all populations) exposure scenario was derived from the results of a high

- quality, well

- conducted CCA rat study (MRID 46025406 ). A BMDL 10 

### of 1.99 mg/kg/day

associated with RBC AChE inhibition following a single oral exposure i n adult females (day 42) was selected as a suitable POD for the acute dietary (all populations) exposure scenario. The corresponding BMD 10 

### was 3.17 mg/kg/day.

RBC AChE inhibition was selected for the POD since RBCs are a principal target for OP pestic ides and the RBC AChE data were more sensitive than the brain AChE data. Data from the adult females represent the lowest BMD 10 

### and BMDL 10 

### values obtai ned following a single dose compared to juveniles (both sexes) and adult males. This endpoint is considered protective of all populations, including children, since there was no quantitative lifestage sensitivity seen in the

database.

An uncertainty factor of 10 0 0X (10X to account for interspecies extrapolation, 10X for intraspecie s variation, and 1 0 X for FQPA SF due to uncertainty in the human dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) ) is applied to the BMDL 10 

### to obtain

an aPAD of 0.0 0 199 mg/kg/day for exposure scenarios with infants, children, you ths, and women of childbearing age. The only population subgroup for which the FQPA SF is not

retained is adults 50

- 99; therefore

, the aPAD for this population subgroup is 0.0199 mg/kg/day.

Steady

- State Dietary (all populations)

There is remarkable similarity in BMD estimates across multiple studies, durations, and compartments in studies 10 days and longer in adult rats (Table 4.3.1.1 and Appendix C). There

was no evidence of increased quantitative susceptibilit y to offspring

. AChE inhibition in juvenile rats was seen at or above dose levels eliciting inhibition in adults. In the DNT studies,

little or no inhibition was seen in fetuses and young juvenile rats at doses causing considerable

AChE inhibition in adult rats. Additio nally, pregnant females were not found to be more

sensitive.

Of the repeated dosing studies, data from the rat combined chronic/carcinogenicity study (MRID 00081685) was found to be the most robust taking into consideration dose spacing and BMD

model resu lts. A BMDL 10 

### of 0.12 mg/kg/day associated with RBC AChE inhibition in male and

female adult rats at the 13 week interim measurement was selected as a suitable POD for thePage 23 of 57 

### steady

- state dietary (all populations) exposure scenario. The corresponding BMD 10 

### was 0.14 mg/kg/day and 0.13 mg/kg/day in males and females, respectively. Similar BMDL 10 

### values were obtained in the repeat CCA study, in non

- pregnant females in the DNT studies, and at terminal measurements in the rat chronic/carcinogenicity study. Alth ough lower values were obtained in the rat subchronic neurotoxicity and mouse carcinogenicity studies, poor dose spacing forced extrapolation to much lower doses in order to obtain BMD 10 

### estimates. The subchronic oral dog study also provided a lower BMD e stimate; however, there was large variability noted at all doses and inspection of the data found no AChE inhibition at the BMD 10 

### estimates generated. As a result, the BMD estimates from these studies were not considered appropriate for endpoint

selection

.

An uncertainty factor of 10 0 0X (10X to account for interspecies extrapolation, 10X for intraspecies variation, and 1 0 X for FQPA SF due to uncertainty in the human dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) ) is applied to the BMDL 10 

### to obtain

a ssPAD of 0.00 0 12 mg/kg/day for exposure scenarios with infants, children, youths, and women of childbearing age. The only population subgroup for which the FQPA SF is not retained is

adults 50

- 99; therefore

, the ssPAD for this popu lation subgroup is 0.0012 mg/kg/day.

Incidental Oral, Steady

- State

For the purpose of assessing potential risk associated with incidental oral exposure from steady

state durations, OPP selected the dose and endpoint from the combined chronic/carcinogenic ity study in rats for the reasons outlined above for steady

- state dietary exposures. The selected study is protective of all populations since there was no evidence of increased quantitative susceptibility in repeated dosing studies. A total uncertainty factor of 100 0 X is appropriate for incidental oral exposures (10X for interspecies extrapolation, 10X for intraspecies variation, and

a 1 0 X FQPA SF due to uncertainty in the human dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) ).

Dermal, Steady

- State

A dermal POD was selected from a 21

- day dermal toxicity study (MRID 44999101) in rabbits

based on RBC AChE inhibition. The data were not amenable to BMD modeling 5 

### ; therefore

, the NOAEL of 1 mg/kg/day was selected as the POD for dermal exposures. The LOAEL was 10 mg/kg/day based on RBC AChE inhibition . This study is appropriate for the route and duration of exposure. A total uncertainty factor of 10 0 0X is appropriate for dermal exposures (10X for interspecies extrapolation, 10 X for intraspecies variation, and a 1 0 X FQPA SF for residential

assessments or a database uncertainty factor in occupational assessments due to uncertainty in

the human dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) ).

Inhala tion Steady

- State

5 Data were not amenable to BMD modeling due to a flat dose response with a decreas e only at the highest dose tested and relatively large variability noted at all doses.Page 24 of 57 

### An inhalation POD was selected from a 21

- day inhalation (aerosol) toxicity study based on RBC AChE inhibition. This study is appropriate for the route and duration of exposure. The data

were not amenable to BMD modeling 6 

### ; therefore the LOAEL of 68 mg/m 3 

### was selected as the POD for inhalation exposures. The NOAEL was not established. Due to insufficient characterization of particle sizes in the study, the mass median a erodynamic diameter (MMAD) and geometric standard deviation (GSD) co uld not be determined. As a result, huma n equivalent concentrations could not be estimated for the systemic effe c ts (AChE inhibition) from inhalation exposure. For occupational scenarios, duration adjustments were made to extrapolate exposure

in the anim al study (6 hours/day, 5 days/week) to a typical occupational exposure (8 hours/day, 5 days/week). The resulting duration adjusted value for occupational exposures is 51 mg/m 3 

### . For estimating occupational inhalation risks from different occupational acti vities, inhalation doses of 2.90, 5.84, and 10.14 mg/kg/day corresponding to the breathing rates of 8.3, 16.7, or 29 L/min were calculated using this duration adjusted value. For occupational inhalation exposures, the

maximum total uncertainty factor of 3 000X was applied (10X for interspecies extrapolation, 10X for intraspecies variation, and 3 0X database uncertainty factor to incorporate uncertainty in the

human dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) and the UF L 

### due to lack of a NOAEL ).

4. 6 .2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources (oral, dermal, and inhalation) and determine whether the individual exposures can be combined if they have t he same toxicological effects. PODs for the incidental oral, dermal, and inhalation routes are all derived from RBC AChE inhibition. As a result, exposure from all routes can be combined.

4. 6 .3 Cancer Classification and Risk Assessment Recommendation

Profenofos is classified as a “Group E Chemical

– evidence of non

- carcinogenicity for humans” based on lack of evidence of carcinogenicity in rats and mice. Therefore, a quantitative cancer risk assessment is not required

.

4. 6 .4 Summary of Points of Dep arture and Toxicity Endpoints Used in Human Risk

Assessment

Table 4. 6 .4.1. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Dietary and Non

Occupational Human Health Risk Assessments. Exposure/

Scenario POD UFs a LOC Study and Toxicological Effects

Acute Dietary (all populations except adults

50

- 99 years) BMDL 10 = 1.99 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 0 X aRfD = 0.0 0 199

aPAD = 0.0 0 199 Acute CCA study in rats (MRID 46025406)

BMD 10 = 3.17 mg/kg/day

.

6 Mortality at the highest dose tested left only two treatment groups for modeling and dose selection forced extrapolation to a much lower value from the lowest dose to obtain a BMD 10

.Page 25 of 57 Table 4. 6 .4.1. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Dietary and Non

Occupational Human Health Risk Assessments. Exposure/

Scenario POD UFs a LOC Study and Toxicological Effects

Inhibition of RBC AChE in adult female

rats.

Acute Dietary (adults 50

- 99 years) BMDL 10 = 1.99 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aRfD = 0.0199

aPAD = 0.0199 Acute CCA study in rats (MRID 46025406)

BMD 10 = 3.17 mg/kg/day

.

Inhibition of RBC AChE in adult female

rats.

Steady

- State Dietary (all populations except adults

50

- 99 years) BMDL 10 = 0.12 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 0 X ssRfD = 0.0 0 012

ssPAD = 0. 0 0012 Combined chronic oral toxicity/carcinogenicity study (MRID 00081685)

BMD 10 = 0.14/0.13 mg/kg/day (males/females)

.

Inhibition of RBC AChE in adult rats at 13

week interim measurement.

Steady

- State Dietary (adults 50

- 99 years) BMDL 10 = 0.12 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X ssRfD = 0.0012

ssPAD = 0.0012 Combined chronic oral toxicity/carcinogenicity study (MRID 00081685)

BMD 10 = 0.14/0.13 mg/kg/day (males/females)

.

Inhibition of RBC AChE in adult rats at 13

week interim measurement.

Incidental Oral Steady

- State BMDL 10 = 0.12 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 0 X Residential LOC

for MOE < 10 0 0 Combined chronic oral toxicity/carcinogenicity study (MRID 00081685)

BMD 10 = 0.14/0.13 mg/kg/day (males/females)

.

Inhibition of RBC AChE in adult rats at 13

week interim measurement.

Dermal Steady

- State NOAEL = 1 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 0 X Residential LOC

for MOE <10 0 0 21

- day rabbit dermal toxicity (MRID 41644501)

LOAEL = 10 mg/kg/day

.

Inhibition of RBC AChE in adult rabbits. Cancer (oral, dermal, inhalation) Classification: Group E Chemical

– evidence of non

- carcinogenicity for humans

.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, ss = steady

- state). RfD = reference dose (a = acute, ss = steady

- state). MOE =Page 26 of 57 margin of exposure. LOC = level of concern. BMD = benchmark dose. BMDL = lower 95% confidence interval

for benchmark dose.

a FQPA SF retained for infants, children, youths, and women of childbearing age for all exposure scenarios due to uncertainty in the human dose

- response relation ship f or neurodevelopmental effects (s ee Section 4.4)

. This includes all exposure scenarios, except the dietary exposure scenarios for the population subgroup adults 50

- 99 for which the FQPA SF has been reduced to 1X

.

Table 4. 6 .4.2. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Occupational Human

Health Risk Assessments. Exposure/

Scenario POD UFs LOC Study and Toxicological Effects

Dermal Steady

- State NOAEL = 1 mg/kg/day UF A = 10X

UF H = 10X

UF DB = 10X b Occupational

LOC for MOE

< 100 0 21

- day rabbit dermal toxicity (MRID 41644501)

LOAEL = 10 mg/kg/day

.

Inhibition of RBC AChE in adult rabbits.

Inhalation Steady

- State LOAEL = 68 mg/m 3 /day a UF A = 10X

UF H = 10X

UF DB = 3 0X c Occupational

LOC for MOE

< 3 000 21

- day inhalation rat study (MRID 00082079)

LOAEL = 68 mg/m 3 /day

.

Inhibition of RBC AChE in adult rats. Cancer (oral, dermal, inhalation) Classification: Group E Chemical

– evidence of non

- carcinogenicity for humans

.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lo west

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = database uncertainty factor for

e xtrapolation from a LOAEL to NOAEL. MOE = margin of exposure. LOC = level of concern. BMD =

benchmark dose. BMDL = lower 95% confidence interval for benchmark dose.

a Inhalation doses corresponding to the breathing rates of 8.3, 16.7, and 29 L/min we re calculated as 2.90, 5.84, and 10.14 mg/kg/day, respectively, for occupational activities using a duration adjusted value of 51 mg/m 3

. b UF DB for occupational dermal exposures = database uncertainty factor for uncertainty in the human dose

- response relat ionship f or neurodevelopmental effects (s ee Section 4.4)

.

c UF DB for occupational inhalation exposures = database uncertainty factor incorporating uncertainty in the human

dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4) and the UF L due to lack of a NOAEL in the subchronic inhalation toxicity study.



### 4. 7 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carc inogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints that may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cy clicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects inPage 27 of 57 

### differen t taxonomic groups. As part of its reregistration decision for profenofos, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 4 08(p), profenofos is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 con sists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential t o interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- rela ted effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued te st orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 7 

### and includes some pesticides sche duled for Registration Review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

Profenofos is on List 2. List 2 represents the next set of chemicals for which EPA intends to

issue test orders/data call

- ins in the near future. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website

. 8



### 5.0 Diet ary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The requirement for plant metabolism is fulfilled based on acceptable cotton metabolism studies depicting the metabolism of p rofenofos in cotton following foliar treatment. Profenofos is metabolized in cotton primarily to a glucosyl sulfate conjugate of 4

- bromo

- 2

- chlorophenol. Profenofos and the glucosyl sulfate conjugate of 4

- bromo

- 2

- chlorophenol are the predominant

residues of profenofos in cotton. The results of the cotton metabolism study were presented to

7 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

8 http://www.epa.gov/endo/Page 28 of 57 

### the HED Metabolism Committee (7/28/95) which concluded that profenofos per se is the residue of concern in cotton for tolerance enforcement and risk assessment purposes.

The requirements for livestock metabolism are fulfilled. Acceptable ruminant and poultry

metabolism studies have been submitted and evaluated. The HED Metabolism Co mmittee (7/28/95) concluded that profenofos per se is the compound of toxicological concern in milk and

ruminant tissues. The Committee also concluded that there is no reasonable expectation of finite residues of profenofos in poultry tissues or eggs. Re sidues of profenofos were not present in any of the poultry tissues analyzed (meat, fat, or eggs), even at exaggerated dosing levels. Thus, there is presently no need to establish tolerances for residues of profenofos in poultry tissues or

eggs.

The requ irement for a confined rotational crop study is fulfilled. An acceptable study was submitted that adequately demonstrat es residues of concern are not likely to be found in appreciable concentrations in crops planted in as little as 30 days after treatment . The 30

- day plant back interval ( PBI ) on the label is adequate

.

5.1.2 Summary of Environmental Degradation

Profenofos degrades primarily by microbial metabolism as well as the abiotic process of hydrolysis. Aerobic and anaerobic soil metabolism half

- lives are similar, 2.3 and 2.1 days respectively. Degradation due to hydrolysis varies with pH, with half

- lives ranging from 107

- 475 days for acidic (pH 5) waters, 24.4

- 69.9 days for waters with neutral pH (pH 7), and 0.32

- 0.43 days for alkaline waters (pH 9). The half

- life of profenofos, under anaerobic aquatic conditions, due to metabolism is 3.8 days at 25 °C. The values of the photolysis half

- life were compared to the hydrolysis half

- lives at pH 5. The dark corrected photolysis half

- life was found to be 266 days. An available laboratory study indicates that profenofos has a slight mobility potential to leac h in soils.

The predominant degradate of profenofos observed in laboratory studies (including hydrolysis, photolysis, and metabolism) was 4

- bromo

- 2

- chlorophenol, which was formed by hydrolysis of the organophosphate group from the phenyl ring of profenof os. Also formed in equimolar parts with degradate O

- ethyl

- S

- propyl phosphorothioate; however, profenofos, is the only residue of

concern for the human health risk assessment.

5.1.3 Comparison of Metabolic Pathways

In plants, profenofos is metabolized primarily to a glucosyl sulfate conjugate of 4

- bromo

- 2

- chlorophenol. In goat and poultry tissues and in rats , residues consist primarily of 4

- bromo

- 2

- chlorophenol and its sulfate. None of the primary metabolites in either plant or goat and poultry

tissue s ; e.g., 4

- bromo

- 2

- chlorophenol, 4

- bromo

- 2

- chlorophenol sulfate and 4

- bromo

- 2

- chlorophenol sulfate glucosyl conjugate, are AChE inhibitors. Furthermore, metabolism and feeding studies indicate that residues of profenofos are found in the milk, fat

, and liver of ruminants, only. No profenofos is found in poultry tissues or eggs even at exaggerated feeding

levels.Page 29 of 57 

### 5.1.4 Residues of Concern Summary and Rationale

Ta b le 5.1.4 .1

. Su mm a r y o f Me tabolit e s a n d D e g r a d at e s to be i n c l ud e d in t h e Risk Ass e s s m e n t and Tole r a n c e Ex p re ss i on.

M a trix R esi d u es i n cl u d ed in R i s k As s e ss m e n t R esi d u es i n cl u d ed in T o l e r a n ce E x pr es s i o n

P la n ts P r i m a r y C ro p P rofenofos per se P rofenofos per se

R o tati o n al C ro p P rofenofos per se P rofenofos per se

L i v esto c k R u m i n a n t P rofenofos per se P rofenofos per se

P o u ltry N o t A pp lica b le 1 N o t A pp lica b le 1

D r i n k i n g W ater P rofenofos per se N o t A pp lica b le

1 CFR 180.6(a)(3) (Category 3). If new uses are registered that would result in a higher dietary burden, Category 3 may no longer apply (Results of Metabolism Committee, 28

- JUL

- 1995; No DP#).



### 5.2 Food Residue Profile

H E D h a s p r e vious l y e v a l u a ted re sidue d a ta d e p i c t i ng the m a g ni t ude o f profenofos r e sidues of

c on ce rn in/on c o t t ons e e d a nd c ot t on g in b y prod uc ts. The a ppl i ca t i on r a tes r e pr e s e nt 1X the

ma x i m um r e g is t e r e d r a t e s and the minimum PHI of 14 days. Profenofos residues in/on treated cottonseed ranged from <0.05 ppm (nondetectable) to 1.1 ppm. Residues were observed to concentrate marginally 1.4 X in cottonseed hulls, and no concentration of residues were observed in cottonseed meal and refined, bleached, and deodorized oil.

5.3 Wat er Residue Profile

The residues of concern in drinking water for purposes of risk assessment are profenofos. EFED provided EDWCs for profenofos in the following drinking water assessment, “Drinking Water Assessment for Profenofos for Registration Review ( M. Colletti ; D425755). EFED noted that no current monitoring data are available for profenofos. The current drinking water assessment

relies on modeled estimates. The recommended EDWCs for profenofos are based on the only currently registered use site, cotton, which is grown in several states. The percent cropped area (PCA) for cotton, 0.21, was used for a national assessment.

EFED provided both surface (from the SWCC version 1.106 (EFED, 2014) model) and groundwater (Pesticide Root Zone Model for Groundwater (PRZM

- GW) , version 1.0, August 31, 2012 ) EDWC s . EFED stated that the surface water EDWC was appropriate to use in the acute dietary exposure assessment. For the steady

- state dietary exposure assessment, EFED

pro vided daily time

- series outputs that simulate 29 years of residues of profenofos in drinking

water. These distributions were adjusted so that the data points were 21

- day rolling averages

. These values were incorporated into RDFs for use in DEEM

.

Surface Water Modeling for Acute Assessment

For Tier 2 surface water assessments, the SWCC model was used to calculate the EDWCs of the active ingredient profenofos in surface waters. The Tier 2 assessment reports the EDWCs for profenofos that are expected once every ten years. The estimates are generated using 30

- years of meteorological data, encompassi ng the years from 1961 to 1990. For further information onPage 30 of 57 

### these models see: http://www.epa. gov/oppefed1/models/water/index.htm

. The profenofos concentrations simulated by SWCC assume tha t 100% of the watershed is planted to the simulated crop. The r aw SWCC concentrations (output) are then multiplied by the PCA factor

for cotton to account for the less than 100% coverage by the crop in a watershed large enough to support a drinking water facility. The SWCC output concentrations multiplied by the PCA are the EDWCs. PCAs are the maximum proportion of a drinking water basin that might be planted with a specific crop (EFED, 2014) . The PCA for cotton was determined to be 0.21.

The recommended EDWCs modeled using the Tier II SWCC for the surface water drinking water exposure assessment for Registration R eview are 5.92 μg/L (ppb) for the peak concentration, 0.283 μg/L for the annual mean concentration, and an overall mean concentration

of 0. 167 μg/L. The highest peak concentration, the highest annual, and overall mean values

occurred with the Texas cotton OP scenario.

Table 5.3.1. EDWC of Profenofos Residues for Cotton in an Index Reservoir with the SWCC Model.

1

- in

- 10 year Profenofos Concentration (μg/L) Concentration (μg/L)

Scenario

- State Crop 1,2 Peak Annual Mean Overall Annual Mean

CA

- Cotton 0.527 0.0382 0.0365

MS

– Cotton 4.87 0.214 0.113

NC

- Cotton 4.43 0.206 0.0945

TX

- Cotton 5.92 0.283 0.167

1 The bold value represent s the recommend EDWCs to be use in the acute drinking water assessment.

2 The simulations used the maximum labeled number (10) of applications and application rate (0.5 lb

ai /A/application), and a maximum seasonal application rate (5 lb ai /A). The concentrations have been adjusted with the Percent Cropped Area (PCA) of 0.21 fo r cotton for a national assessment.



### Drinking Water Estimates for Steady

- State Assessment

For the steady

- state assessments, EFED provided daily time

- series outputs that simulate 29 years of residues of profenofos in drinking water for the following 5 cott on application scenarios: TX cotton reservoir; MS cotton reservoir; MS cotton reservoir ; NC cotton reservoir; and CA cotton reservoir. Each scenario was run individually in DEEM. These distributions were adjusted so that the data points were 21

- day roll ing averages and these values were incorporated into RDFs

for use in DEEM for “water direct all sources” and “water indirect all sources.” In the 21

- day rolling average distributions, the first data point is the average of days 1

- 21, the second data point is the average of days 2

- 22, the third data point is the average of days 3

- 23, etc. The 21

- day rolling average continues until the last 20 days of residues of the final distribution year (1990). For these residues, the average was taken only of the rema ining days, resulting in

residue values that are not 21

- day averages. This is not expected to have a large impact on the dietary exposure assessment since the data points which are not true 21

- day rolling averages represent only 20 days out of 29 years an d the simulated drinking water estimates do not include applications at the end of the year.

5.4 Dietary Risk Assessment

Profenofos acute and steady

- state dietary exposure assessments were conducted using DEEM

FCID, Version 3.16, which incorporates con sumption data from USDA’s N HANES/WWEIA.Page 31 of 57 

### This dietary survey was conducted from 2003 to 2008. The analyses w ere performed to support

the Re gistration R eview of profenofos.

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute dietary exposure assessmen t was conducted using tolerance level residues (HED’s recommended 3.0 ppm for cottonseed for purposes of harmonization) , DEEM default processing factors, and assumed 100% CT. T he steady

- state dietary exposure assessment assumed an

averag e field trial value for cotton (Memo, C. Eiden, 01

- AUG

- 1995; D217739), cottonseed oil processing factor (Memo, C. Eiden, 01

- AUG

- 1995; D217744), and tolerance level residues and

DEEM default processing factors for meat and milk commodities. The cotton PCT was applied

to cotton and all meat/milk commodities. RDFs were used for milk and meat commodities.

5.4.2 Percent Crop Treated Used in Dietary Assessment

A Screening Level Usage Analysis (SLUA) memo was provided by BEAD; however, HED did

not use the PCT in the acute assessment as the unrefined results were <100% aPAD at the 9 5 th


### percentile of exposure. The acute aggregate dietary analyses were performed as suming 100% of each commodity was treated with profenofos. For the steady

- state assessments (food only and food + drinking water), PCT for cotton (1%) was applied to cotton and all meat and milk

commodities. Results are therefore presented up to the 99.9 th 

### percentile of exposure. PCT was not applied to drinking water; therefore when drinking water only is discussed, results are

discussed at the 95 th 

### percentile of exposure.

5.4.3 Acute Dietary Risk Assessment

The acute assessment is not considered to be a refined assessment as anticipated residues, monitoring data, PCT data, empirical processing factors, cooking factors derived from literature studies, or refined drinking water values were not incorporated. T olerance level residues (HED’s

recommended 3. 0 ppm for cottonseed for purposes of harmonization)

, DEEM (ver. 7.81) default processing factors, and 100% CT data were utilized.

T he unrefined acute dietary (food + drinking water) exposure analysis is <100 % aPAD at the 95th percentile of exposure for the general population and all population subgroups (Table 5.4.3.1) . Children 1

- 2 years old was the population subgroup with the highest exposure ( 80 % of

the aPAD at the 95 th 

### percentile).

Table 5.4.3.1. Summary of Acute Die tary (Food + Drinking Water

– TX Cotton Reservoir Scenario) Exposure and Risk for Profenofos 1

. Population Subgroup aPAD ( mg/kg/day ) 2 95 th Percentile Exposure ( mg/kg/day ) % aPAD

General U.S. Population

0.00199 0.000746 38

All Infants (<1 year old) 0.001311 66

Children 1

- 2 years old 0.001595 80Page 32 of 57 Table 5.4.3.1. Summary of Acute Die tary (Food + Drinking Water

– TX Cotton Reservoir Scenario) Exposure and Risk for Profenofos 1

. Population Subgroup aPAD ( mg/kg/day ) 2 95 th Percentile Exposure ( mg/kg/day ) % aPAD

Children 3

- 5 years old 0.001306 66

Children 6

- 12 years

old 0.000907 46

Youth 13

- 19 years old 0.000574 29

Adults 20

- 49 years

old 0.000527 26

Adults 50

- 99 years

old 3 0.000461 2.3

Females 13

- 49 years

old 0.000524 26

1 Highest exposure at the 95 th percentile is in bold.

2 aPAD = acute population

- adjusted dose.

3 Subpopulation adults 50

- 99 years old: aPAD = 0.0199 mg/kg/day

.



### 5.4.4 Steady

- State Dietary Risk Assessment

S teady

- state assessments were conducted in the DEEM acute module using the steady

- state endpoint and 21

- day rolling water averages to provide an estimate of 21

- day (“steady

- state”) average daily exposures. S teady

- state assessments were conducted for drinkin g water alone, food alone, and food + drinking water. The se steady

- state assessments are not considered to be highly refined assessments as they did not incorporate monitoring data or empirical processing/cooking

factors . Cottonseed oil is considered a blended commodity; therefore, HED utilized an average field trial residue, an average processing factor, and PCT. Meat and milk commodities are not considered blended commodities; therefore, the tolerance level, along wit h PCT were incorporated into an RDF that was used in DEEM for the appropriate meat and milk commodities. EFED provided daily time

- series outputs that simulate 29 years of residues of profenofos in drinking water for 5 different cotton application scenario s. These distributions

were converted into 21

- day rolling averages and incorporated into RDFs that were used in

DEEM for direct all sources and indirect all sources.

For the steady

- state food alone exposure estimates, results are shown at the 99.9 th 

### per centile as PCT was incorporated into the food residue files

. C hildren 1

- 2 years old are the highest exposed subpopulation at 350% of the ssPAD (99.9 th 

### percentile of exposure)

. For drinking water only

, t he 95 th 

### percentile is shown as no PCT was incorporated. EFED provided a total of five drinking

water scenarios. Four out of the five drinking water only scenarios had at least one subpopulation that was >100% ss PAD at the 95 th 

### percentile (CA cotton scenario had estimates

< 100% for all populations at the 95 th 

### percentile). The subpopulation “all infants (<1 year old)” was the highest exposed population for all five drinking water only scenarios at all percentiles. For CA cotton (the lowest exposure scenario), all infants (< 1 year old) utilized 52% of the ssPAD and for TX cotton (the highest exposure scenario), all infants (<1 year old) utilized 220%

of the ssPAD at the 95 th 

### percentile. For the food + drinking water exposure estimates, results are

shown at the 99.9 th 

### percent ile as PCT was incorporated into the food residue files. All five food + drinking water scenarios are of concern to HED (>100% ssPAD). The TX scenario had the overall highest exposure estimates (all infants (<1 year old) as the highest exposed population subgroup at the 99.9 th 

### percentile with 1600% of the ssPAD). The CA cotton scenario had thePage 33 of 57 

### overall lowest exposure estimates (children 1

- 2 years old was the highest exposed population subgroup at the 99.9 th 

### percentile with 3 6 0% of the ssPAD). The other three food + drinking water scenarios were similar to (but lower than ) the TX scenario.

The results for all population subgroups and drinking water scenarios (general U.S. p opulation

, all infants (< 1 year old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19, females 13

- 49,

adults 20

- 49, and adults 50

- 99 years) are summarized in the most recent dietary exposure assessment memorandum (S. Levy; 1 5

- SEP

- 2015 ; D427269 ).

Table 5.4.4.1. Summary of Steady

- State Dietary (Food Only) Exposure and Risk for Profenofos 1

. Population Subgroup ssPAD ( mg/kg/day ) 2 95 th Percentile 99 th Percentile 99.9 th Percentile Exposure ( mg/kg/day ) %

ssPAD Exposure ( mg/kg/day ) %

ssPAD Exposure ( mg/kg/day ) %

ssPAD

General

U.S. Population

0.00012 0.000003 2.2 0.000025 21 0.000115 96

All Infants (<1 year old) 0.000002 1.3 0.000034 29 0.000217 180

Children

1

- 2 years

old 0.000013 11 0.000162 130 0.000421 350

Children

3

- 5 years

old 0.000009 7.9 0.000091 76 0.000232 190

Children

6

- 12 years

old 0.000006 4.9 0.000051 4 2 0.000144 120

Youth 13

- 19 years

old 0.000003 2.2 0.000026 21 0.000084 70

Adults 20

- 49 years

old 0.000002 1.7 0.000019 16 0.000067 56

Adults 50

- 99 years

old 3 0.000002 <1.0 0.000017 1.4 0.000055 4.6

Females

13

- 49 years old 0.000002 1.6 0.000019 15 0.000064 53

1 Highest exposure at the 99.9th percentile is in bold.

2 ssPAD = steady

- state population

- adjusted dose.

3 Subpopulation adults 50

- 99 years old: ssPAD = 0.0012 mg/kg/day

.Page 34 of 57 Table 5.4.4.2. Summary of Steady

- State Dietary Exposure and Risk for Profenofos 1

.

Drinking Water

Scenario Steady

- State DRINKING WATER ONLY (All Infants <1 year old) Steady

- State FOOD + DRINKING WATER Highest Exposure Estimate

95 th 99.9 th
Population Subgroup 2 99.9 th

Exposure ( mg/kg/day ) % ssPAD Exposure ( mg/kg/day ) % ssPAD Exposure ( mg/kg/day ) % ssPAD

MS Cotton reservoir 0.000227 190 0.001577 1300 All infants 0.001577 1300

TX Cotton Reservoir 0.000262 220 0.001919 1600 All infants 0.001922 1600

MS Cotton pond 0.000153 130 0.001525 1300 All infants 0.001527 1300

NC Cotton 0.000130 110 0.001352 1100 All infants 0.001342 1100

CA Cotton 3 0.000064 52 3 0.000318 280 3 Children 1

- 2 years old 0.000429 360

1 ssPAD = steady

- state population

- adjusted dose.

2 The results for all population subgroups (general U.S. p opulation , all infants (<1 year old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19, females 13

- 49, adults 20

- 49, and adults 50

- 99 years) for all runs are summarized in the dietary exposur e assessment memorandum (S. Levy; 15

- SEP

- 2015 ; D427269 )

. 3 For reference, drinking water exposure for children 1

- 2 years old was 140 % at the 95 th percentile and 160% at the

99.9 th percentile.



### 5.4.5 Cancer Dietary Risk Assessment

Profenofos is classified as a Group E Chemical based on lack of evidence of carcinogenicity in

rats and mice. Quantitative risk assessment for profenofos using the reference dose approach will adequately account for all chronic toxic effects, including carcinogenic ity.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. There are currently no registered or proposed residential uses for profenofos ; therefore, a residential handler assessment was not performed.

6.2 Post

- Application Exposure

There are currently no registered or proposed residential uses for profenofos ; therefore a

residential post

- application assessment was not performed

. The potential for indirect exposure from spray drift has been assessed below in Section 6.4.Page 35 of 57 

### 7.0 Residential Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to

individuals nearb y pesticide applications. The A gency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010

. 9 

### The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis

. 10 

### D uring Registration Review, the A gency will utilize this analysis to determ ine if data (i.e., flux studies) or further analyses are required for profenofos

.

8.0 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures ( e.g.
, children playing on lawns wher e residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products.

The appro ach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulat ory requirements intended to prevent them. 11 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as resident ial lawns, when com pliant applications are conducted. Given this premise, exposures for children (1 to <2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect

exposure are the focus of th is analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate res idential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of profenofos

. I n the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ® 

### (v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy

. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Res idential Risk Assessment (SOPs)

.

9 http://www.epa.gov/scipoly/SAP/meetings/2009 /120109meeting.html

10 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219

11 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.Page 36 of 57 

### For profenofos, chemical

- specific turf transferable residue (TTR) data are not available, therefore, the estimated TTR are based on a default assumption from the 2012 Residential SOPs

that the transferable residue availab le for exposure is 1% of the total deposited residue, which is assumed to be equivalent to the maximum application rate.

A screening approach was developed based on the use of the AgDrift ® 

### model in situations where specific label guidance that defines a pplication parameters is not available. 12

, 13 

### AgDrift ® 

### is appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and groundboom sprayers. When AgDrift ® 

### was developed, a series of screening values (i.e., the Tier 1 option ) were incorporated into the mod el and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk ass essment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are

not allowed ). Table 6.4 .1 provides the screening level drift related risk estimates. In many cases, risk estimates are of concern when the screening level estimates for spray drift are used as the basis for the analysis. In order to account for this issue and to p rovide additional risk management options, additional spray drift deposition fractions were also considered. These drift estimates represent plausible options for pesticide labels.

Combined Risk Estimates from Lawn Deposition Adjacent to Applications

Th e spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Profenofos is registered on cotton, and can only be applied via enclosed cab groundboom equipment at a rate of 0.5 lb ai/A. The recommended drift scenario screening level options are listed below:

• Groundboom applications are based on the AgDrift ® 

### option for high boom height and using very fine to fine spray type using the 90 th 

### percentile results.

In addition to the screening level spray drift scenarios described above, additional results are provided which represent viable drift reduction technologies (DRTs) that represent potential risk management options. In particular, different spray qualitie s have been considered as well as the impact of other application conditions (e.g., boom height and crop canopy conditions).

Dermal risk estimates were calculated for adults. For adults, when an endpoint is not sex

specific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, a female

- specific body weight of 69 kg

was used. While the endpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

sp ecific body weight was used to protect for pregnant women due to uncertainty in the human

12 http://www.agdrift.com/

13 Note that for many cases the scenarios outline d in the screening approach represent actual use practice so risk assessors should be aware and characterize these appropriately.Page 37 of 57 

### dose

- response relationship f or neurodevelopmental effects (s ee Section 4.4). Dermal and incidental oral risk estimates for children (1 to <2 years old) were combined because the toxicity endpoint for each route of exposure is the same (RBC AChE inhibition). The total applicable LOC is 1000, so MOEs <1000 represent risk estimates of concern.

Risk estimates related to spray drift are of concern at various distances from the edge of the field for adults and children (1 to <2 years) depending on the spray drift scenario. Adult and children

risk esti mates are summarized in Table 8

. 0. 1. For adults, the screening level scenario of a high boom and very fine to fine spray requires a distance of over 300 feet to reach a dermal MOE ≥ 1000. For children, the screening level scenario also requires a distance of over 300 feet to reach a combined (dermal and incidental oral) MOE ≥1000. Drift reduction technologies, such as

usi ng coarser sprays and lowering boom height for groundboom sprayers, reduces risk concerns; however there are still risk estimates of concern at the field edge. Further, c hemical

- specific TTR data could be submitted to help refine the spray drift assessmen t.Page 38 of 57 Table 8.0.1 . Spray Drift Risk Estimate Summary for Profenofos.

Crop / Application Type Spray Type/

Nozzle Configuration Application

Rate (lb ai/A) Estimated

TTRt (ug/cm 2 ) MOE at Different Distances from Edge of Field (Dermal MOE for Adults; Dermal + Incidental Oral MOE for Children 1 to <2 years)

LOC = 1000

At Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 feet 150 feet 200 feet 250 feet 300 feet

Children (1 to <2 years)

Cotton /

Groundboom Screening Level High Boom Very

fine to Fine

0.5 0.056 12 25 41 66 92 110 140 160 210 290 330

Low Boom Very

fine to Fine 27 72 110 180 230 290 330 380 460 570 770

High Boom Fine

to Medium /

Coarse 47 120 180 260 330 380 460 460 570 770 770

Low Boom Fine

to Medium /

Coarse 70 190 290 380 460 570 770 770 1,100 1,100 1,100

Adults

Cotton /

Groundboom Screening Level High Boom Very

fine to Fine

0.5 0.056 25 49 82 130 180 230 270 330 420 570 660

Low Boom Very

fine to Fine 54 140 230 350 460 570 660 770 920 1,100 1,500

High Boom Fine

to
Medium/Coarse 94 240 350 510 660 770 920 920 1,100 1,500 1,500

Low Boom Fine

to
Medium/Coarse 140 380 570 770 920 1,100 1,500 1,500 2,300 2,300 2,300

Bolded values are below the LOC of 1000

.

### Page 39 of 57 9 .0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The registered uses of profe nofos are not anticipated to result in residential

exposure and thus t he acute and steady

- state dietary exposure estimates provided in Section 5.4.3

and 5.4.4 represent the acute and steady

- state aggregate exposure.

Profenofos is classified as a Group E C hemical based on lack of evidence of carcinogenicity in

rats and mice. Quantification of risk using a non

- linear approach will adequately account for all chronic toxicity, including carcinogenicity that could res ult from exposure to profenofos.

10 .0 Cumulative Exposure/Risk Characterization

OPs, like profenofos, share the ability to inhibit AChE through phosphorylation of the serine residue on the enzyme leading to accumulation of acetylcholine and ultimately cholinergic neurotoxicity. This shared M OA/AOP is the basis for the OP common mechanism grouping per

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999). The 2002 and 2006 CRAs used brain AChE inhibition

in female rats a s the source of dose response data for the relative potency factors and PODs for each OP, including profenofos. Prior to the completion of Registration Review, OPP will update the OP CRA on AChE inhibition to incorporate new toxicity and exposure informat ion available

since 2006.

As described in Section 4.4, OPP has retained the FQPA Safety Factor for OPs, including profenofos, due to uncertainties associated with neurodevelopmental effects in children and exposure to OPs. There is a lack of an establis hed MOA/AOP for the neurodevelopment

outcomes which precludes the agency from formally establishing a common mechanism group per the Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) ba sed on that outcome. Moreover, the lack of a recognized MOA/AOP and other uncertainties with exposure assessment in the epidemiology studies prevent the agency from establishing a causal relationship between OP exposure and neurodevelopmental outcomes. T he agency will continue to evaluate the epidemiology studies associated with neurodevelopmental outcomes and OP exposure prior to the release of the revised DRA. During this period, the agency will determine whether or not it is appropriate to apply the d raft guidance document entitled, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis for the neurodevelopment outcomes.

11 .0 Occupational Exposure/Risk Characterization

11 .1 Short

- and Intermediate

- T erm Handler Risk

HED uses the ter m handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requir ements (amount of chemical used in each application), the kinds of equipment used, the target being

### Page 40 of 57 treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

The quantitati ve exposure/risk assessment developed for occupational handlers is based on the following scenarios which cover all the registered use of profenofos:

• Mixing/loading liquids using closed loading systems to support groundboom applications, and

• Applying spra ys with closed cab groundboom equipment.

Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Assumptions and factors, as well as alg orithms used to estimate non

cancer exposure and dose for occupational handlers are detailed in the most recent occupational and residential exposure ( ORE ) assessment memo (K. Lowe; 15

- SEP

- 2015; D427268).

The steady

- state approach is appropriate for profenofos given the toxicological and exposure profile. The steady

- state endpoint selection for profenofos overlaps with HED’s traditional

short

- term exposure duration endpoint selection and is considered health protective for occupational handlers that apply commercially over longer periods of time (i.e., intermediate

term exposures).

The registered profenofos label requires a closed mixing/loading system and an enclosed cab. In addition, mixer, loaders, applicators, and other handlers using a closed s ystem must also wear long sleeved shirt, long pants, shoes plus socks, chemical

- resistant gloves, chemical

- resistant apron (for mixing and loading), and protective eyewear. Estimates of dermal and inhalation exposure were calculated assuming the use of en gineering controls as required by the label.

For adults, when an endpoint is not sex

- specific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case,

a female

- specific body weight of 69 kg was used. While the endpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

- specific body weight was used to protect for pregnant women due to uncertainty in the human dose

- response relationship f or neurode velopmental effects (s ee Section 4.4).

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates A total ARI was used since the LOC values for dermal exposure (1000) and inhalation exposure (3000) are different. The target ARI is 1; theref ore, ARIs of less than 1 are risk estimates of

concern. The ARI was calculated as follows.

Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]



### Summary of Occupational Handler Non

- Cancer Exposure and Risk Estim ates The occupational handler exposure and risk estimates indicate that the dermal and inhalation combined MOEs are of concern to HED (i.e., ARI <1) for all scenarios. ARIs range from 0.08 to 0.14 using HED defaults for area treated per day (i.e., 200 a cr es for high

- acreage crops such as cotton), and from 0.1 to 0.17 using an adjusted area treated per day (160 acres) to account for the label restriction on the maximum amount of ai that can be handled per day (10 gallons of product or 80 lb ai per day; see Table 3.3.1) . Table 11 .1.1 provides a summary of the occupational

handler risk estimates.

### Page 41 of 57 Table 11 .1.1. Summary of Occupational Handler Risk Estimates for Profenofos.

Exposure

Scenario Crop / Target Category App

Rate 2 Area

Treated 3 Engineering Control Unit Exposure

(ug/lb ai) 1 Engineering Control Dose (mg/kg/day) Engineering Control

MOE Engineering

Control

ARI 8 Dermal Inhalation Dermal 4 Inhalation 6 Dermal 5
(LOC =

1000) Inhalation 7
(LOC =

3000) Mixing / loading liquids for groundboom application

Cotton 0.5 lb

ai/A 200

acres 8.6 0.083 0.0125 0.00012 80 85,000 0.08

Applying via groundboom 5.1 0.043 0.00739 0.0000623 140 160,000 0.14

Mixing / loading liquids for groundboom application 160

acres 8.6 0.083 0.00997 0.0000962 100 110,000 0.1

Applying via groundboom 5.1 0.043 0.00591 0.0000499 170 200,000 0.17

Bolded values are below the LOC (dermal = 1000 and inhalation = 3000) or the combined ARI estimate is < 1

. 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013]); Level of mitigation: Eng. Controls.

2 Based on registered label (Reg. No. 100

- 669).

3 Exposure Science Advisory Council Policy #9.1 and information provided on labels regarding maximum amount of product that can be

handled by mixers/loaders per day (10 gallons). More detailed information regarding the acres assessed can be found in the most recent ORE memo (K. Lowe; 15

- SEP

- 2015; D427268)

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷

BW (69 kg).

5 Dermal MOE = Dermal POD (1 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μ g) × Application Rate (lb ai/acre) × Area Treated

(A/day) ÷ BW (69 kg). 7 Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation PODs (2.90, 5.84, and 10.14 mg/kg/ day) related to breathing rates (8.3, 16.7, or 29 L/min).

8 ARI = Aggregate Risk Index = 1 ÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].



### 11 .2 Short

- /Intermediate

- Term Post

- Application Risk

11 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential s ources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain
pest icides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 14 

### . The Agency has evaluated the SAP report and has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Analysis 15



### . During Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies ) or further analysis is required for profenofos

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by ARTF . Given these two efforts, the Agency will continue to identify

14 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

15 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 201 4

- 0219.

### Page 42 of 57 the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the A gency's risk assessments.

11 .2.2 Occupational Post

- A pplication Dermal Exposure/Risk Estimates

Occupational Post

- application Dermal Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational
post

- application risk assessments. Assumptions and factors, as well as the algorithms used to

estimate non

- cancer exposure and dose for occupational post

- appl ication workers are detailed in the most recent ORE memo (K. Lowe; 15

- SEP

- 2015 ; D427268).

The steady

- state approach is appropriate for profenofos given the toxicological and exposure profile. The “steady

- state” endpoint selection for profenofos overlap s with HED’s traditional

short

- term exposure duration endpoint selection as well as being appropriately health protective for workers that are exposed over longer periods of time (i.e., intermediate

- term exposures).

Chemical

- specific DFR and dislodgeable cotton boll data have been submitted for profenofos. Three DFR studies were submitted that examined residues of profenofos on cotton foliage in various locations: California (MRID 4281303 ), Texas (MRID 4281303 ), and North and South Carolina (MRID 4281302 ). One of these studies (MRID 4281302 ) also examined residues of profenofos on cotton bolls collected after treatment. All three studies have been reviewed by HED and found to be acceptable for risk assessment.

A summary of the results of the availabl e studies and a description of how the DFR and cotton boll data were used is discussed in the most recent ORE memo (K. Lowe; 15

- SEP

- 2015 ; D427268).

For adults, when an endpoint is not sex

- specific (i.e., the endpoints are based on developmental

or fetal e ffects) a body weight of 80 kg is typically used in risk assessment; however, in this case,

a female

- specific body weight of 69 kg was used. While the endpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

- specific body weight was used to protect for pregnant women due to uncertainty in the human dose

- response relationship for neurodevelopmental

effects (s ee Section 4.4).

Occupational Post

- application Non

- Cancer Dermal Risk Estimates

Tables 11 .2.2.2 and 11 .2.2.3 provide summaries of the exposure and risk estimates for post

application activities associated with cotton. Even though the profenofos label requires mechanical harvesting, there are post

- application activities associated with mechanical harvesting that can result in potential exposure. These activities have been assessed using the

available cotton boll residue data.

Based on the current exposure assessment, post

- application risk estimates remain a concern (i.e., MOEs <1000) up to 4 days after applicati on for hand weeding and up to 9 days after application for scouting. Post

- application risk estimates associated with harvesting activities are a concern (MOEs <1000) 14 days after treatment, which would be the earliest harvesting could occur after applica tion based on the current PHI ( see Table 3.3.1 ). An additional calculation was performed to estimate post

- application exposure and risk using the cotton boll residue data from the day of sampling (day 44); however, there were still risk estimates of conce rn for all harvesting activities even 44 days after application at which point residue values were less than the LOQ in the study.

### Page 43 of 57 Table 11 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Profenofos on

Cotton.

Activities Transfer

Coefficient

(cm 2 /hr) Site Days after application DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3
(LOC = 1000)

Hand weeding 70 CA 0 (12 hours) 1.72 0.0121 83

1 0.45 0.0031 320

2 0.22 0.0015 650

3 0.17 0.0012 830

4 0.13 0.0009 1,100

TX 0 (12 hours) 2.44 0.020 51

1 0.33 0.003 380

2 0.11 0.001 1,200

Cheraw, SC 0 (12 hours) 2.25 0.018 55

1 0.46 0.0037 270

2 0.094 0.00076 1,300

Chesterfield, SC 0 (12 hours) 2.99 0.024 41

1 1.20 0.0098 100

2 0.483 0.0039 260

3 0.194 0.0016 640

4 0.078 0.00063 1,600

NC 0 (12 hours) 2.69 0.022 46

1 0.26 0.0021 480

2 0.02 0.00020 5,000

Scouting 210 CA 0 (12 hours) 1.72 0.0362 28

1 0.45 0.0094 110

2 0.220 0.0046 220

3 0.171 0.0036 280

4 0.133 0.0028 360

5 0.104 0.0022 460

6 0.081 0.0017 590

7 0.063 0.0013 760

8 0.049 0.0010 970

9 0.038 0.0008 1,300

TX 0 (12 hours) 2.44 0.059 17

1 0.33 0.008 130

2 0.11 0.003 390

3 0.08 0.002 510

4 0.06 0.001 670

5 0.05 0.001 880

6 0.04 0.059 1,200

Cheraw, SC 0 (12 hours) 2.25 0.055 18

1 0.46 0.011 89

2 0.094 0.0023 440

3 0.019 0.00047 2,100

### Page 44 of 57 Table 11 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Profenofos on

Cotton.

Activities Transfer

Coefficient

(cm 2 /hr) Site Days after application DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3
(LOC = 1000)

Chesterfield, SC 0 (12 hours) 2.99 0.073 14

1 1.20 0.029 34

2 0.483 0.012 85

3 0.194 0.0047 210

4 0.078 0.0019 530

5 2.99 0.00076 1,300

NC 0 (12 hours) 2.69 0.066 15

1 0.26 0.0063 160

2 0.02 0.00060 1,700

Bolded values are below the LOC of 1000

. 1 DFR = Predicted profenofos residues (based on a biphasic regression analysis) adjusted to account for application rate differences. See

Appendix C for more information on DFR study and regression analysis.

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day] ÷ BW ( 69 kg).

3 MOE = POD (1 mg/kg/day) / Dai ly Dermal Dose.

Table 11 .2.2.3. Post

- Application Exposure and Risk Estimates for U se of Profenofos on Cotton D uring Harvesting Activities.

Crop Proposed

Maximum

Seasonal Application Rate (lb ai/A) Activity TC 1 (g cotton

/ hr) Days After

Treatment Cotton boll

residue 2 (ug ai/g cotton) Daily Dose (mg/kg/day) 3 MOE 4
(LOC =

1000)

Cotton 0.5 Harvesting

Mechanical (Module Builder) 900

14 ( PHI ) 4.54 0.474 2.1

Harvesting Mechanical (Picker

Operator; Raker) 2400 1.264 0.79

Harvesting

Mechanical (Tramper) 5050 2.661 0.38

Harvesting

Mechanical (Module Builder) 900

44 (sampling

day in

submitted

study ) 0.26 0.027 37

Harvesting Mechanical (Picker

Operator; Raker) 2400 0.072 14

Harvesting

Mechanical (Tramper) 5050 0.152 6.6

Bolded values are below the LOC of 1000

. 1. Transfer Coefficients from HED Policy No. 3.0., Non

- Foliar Transfer Coefficient Table, March 2012 (p 122).

2. Residue value from MRID 4281302 . On sampling day 44, residues reported as <LOQ (75 ug) and cotton boll sample weighed 1.44 g; therefore, residues = 0.52 ug/g. Per HED policy, 1⁄2

- LOQ value used in calculations (0.26 ug/g). Day 14 (the PHI )

residues were back

- calculated assuming 10% dissipation had occurred per day from day 14 to day 44.

3. Dermal Dose (mg/kg/day) = [Cotton Boll residue, ug ai/g cotton) x TC (g cotton/hr) x hr/day (8 hrs/day)] / BW (69 kg).
4. Dermal MOE = NOAEL (1 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 1000.



### Restricted

- Entry Interval (REI)

The current product

- label REI is 48 hours (72 hours in areas where rainfall is less than 25 inches per year). Under 40 CFR 156.208 (c) (2) (i), ai’s classified as Acute toxicity category I for acute dermal, eye irritation or primary skin irritation are as signed a 48

- hour REI. In addition, for organophosphates that may be applied outdoors in an area where the average annual rainfall for

### Page 45 of 57 the site is less than 25 inches per year, the REI shall be 72 hours. However, based on the current
post

- application derm al exposure assessment, a REI of at least 9 days is necessary for scouting, and a REI of 4 days is necessary for hand weeding. In addition, activities associated with harvesting of cotton are of concern at the current PHI. Increasing the PHI is unlikely to impact

the risk estimates since MOEs for activities associ ated with mechanical harvesting using the Day 44 residue value from the submitted study are still less than the LOC.

12 .0 References

Bouchard MF, Chevrier J, Harley KG, Kogut K, Vedar M, Caldero n N, et al. Prenatal Exposure to Organophosphate Pesticides and IQ in 7

- Year

- Old Children. Environ Health Perspectives. 2011;119:1189

- 1195. Bouchard M.F., Bellinger D.C., Wright R.O., Weisskopf M.G., (2010). Attention

- Deficit/Hyperactivity

Disorder and Uri nary Metabolites of Organophosphate Pesticides. PEDIATRICS DOI:10.1542/peds.2009

- 3058. Chen L, Zhao T, Pan C, Ross JH, Krieger RI. (2012) Preformed biomarkers including dialkylphosphates (DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment. J Agric Food Chem. 2012 Sep 12;60(36):9342

- 51. doi: 10.1021/jf303116p. Epub 2012 Sep 4. Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. Prenatal Organophosphate Metabolite and Organochlorine Levels and Performance on the Brazelton Neonatal Behavioral Assessment Scale in a Multiethnic Pregnancy Cohort. American Journal of Epidemiology. 2007;165:1397

- 1404. Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, Wolff MS. Prenatal Exposure to

Or ganophosphates, Paraoxonase 1, and Cognitive Development in Childhood. Environmental Health Perspectives. 2011;119:1182

- 1188. Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong CE, Holland NT. Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population. Environmental Health Perspectives. 2004;115:792

– 798. Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. Organophosphate Pesticide Exp osure and Neurodevelopment in Young Mexican

- American Children. Environmental Health Perspectives. 2007;115:792

– 798. FIFRA Scientific Advisory Panel. (2012). Transmittal of the Meeting Minutes from the FIFRA Scientific Advisory Panel Meeting of April 10

- 12, 2012. FIFRA Scientific Advisory Panel, Office of Science Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. Available: http://www.epa.gov/scipoly/sap/meetings/2012/041012meeting.htmll Fortenberry, GZ, Meeker, JD, Sánchez, BN, Barr, DB, Panuwet, P, Bellinger, D, Schnaas, L, Solano

González, M, Ettingera, AS, Hernandez

- Avila, M, Hu, H, Tellez

- Rojoj, MM. Ur inary 3,5,6

- trichloro

- 2

- pyridinol (TCPY) in pregnant women from Mexico City: Distribution, temporal variability, and relationship with child attention and hyperactivity. International Journal of Hygiene and Environmental Health 217 (2014): 405

– 412. Forsberg ND, Rodriguez

- Proteau R, Mab L, Morréc J, Christensen JM, Maierc CS, Jenkins JJ, Anderson KA. Organophosphorus pesticide degradation product in vitro metabolic stability and time

course uptake and elimination in rats following oral and intravenou s dosing. Xenobiotica, 2011; 41(5): 422

– 429. Furlong, Melissa A., Engel, Stephanie M., Boyd Barr, Dana, Wolff, Mary S. Prenatal exposure to organophosphate pesticides and reciprocal social behavior in childhood. 2014. Environment

International 70:125

- 13 1. Guodong, Ding, Pei, Wang, Ying, Tian, Jun, Zhang, Yu, Gao, Xiaojin, Wang, Rong, Shi, Guoquan, Wang, and Xiaoming, Shen. Organophosphate Pesticide Exposure and Neurodevelopment in Young Shanghai Children. Environmental Science and Technology 46:2911

- 2917 , 2012.

### Page 46 of 57 Marks AR, Harley K, Bradman A, Kogut K, Barr DB, Johnson C, et al. Organophosphate Pesticide Exposure and Attention in Young Mexican

- American Children: The CHAMACOS Study. Environmental Health Perspectives. 2010;118:1768

- 1774. Oulhote, Youssef and Bouchard, Maryse F. Urinary Metabolites of Organophosphate and Pyrethroid Pesticides and Behavioral Problems in Canadian Children. Environmental Health Perspectives.

121:1378

- 1384 (2013) Racke J.D. Degradation of organophosphorous insecticidesin environme ntal matrices. In: Organophosphates Chemistry, Fate and Effects. Academic Press, Inc., San Diego, CA, 1992, pp

47

– 72. Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt RW. Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner

- City Children. Pediatrics. 2006;18(6): 1835

- 1859. Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. 2011. Seven

- Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyr ifos, a Common Agricultural Pesticide. Environmental Health Perspectives. 2011;119:1196

- 1201. Shelton, Janie F., Geraghty, Estella M., Tancredi, Daniel J., Delwiche, Lora D., Schmidt, Rebecca J., Ritz, Beate, Hansen, Robin L., and Hertz

- Picciotto, Irva. Ne urodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE Study. Environmental Health Perspectives 122:1103

– 1109, 2014. U.S. Environmental Protection Agency. (2008). Draft Science Issue Paper: Chlorpyrifos Hazard and Dose Response Characterization

. http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm U.S. Environmental Protection Agency. (2012). Draft Issue Paper: Scientific Issues Concerning Health Effects of Chlorpyrifos. http://www.regulations.gov/#!d ocumentDetail;D=EPA

- HQ

- OPP

- 2012

- 0040

- 0002 Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, Holland NT. Association Between In Utero Organophosphate Pesticide Exposure and Abnormal

Reflexes in Neonates. NeuroToxico logy. 2005;26:199

– 209. Zhang, Ying, Han, Song, Liang, Duohong, Shi, Xinzhu, Wang, Fengzhi, Wei Liu, Zhang, Li, Chen, Lixin, Gu, Yingzi, Tian, Ying. Prenatal exposure to organophosphate pesticides and neurobehavioral development of neonates: A birth cohort study in Shenyang, China. PlosOne 47:80

– 85, 2014. Zhang X, Driver JH, Li Y, Ross JH, Krieger RI. (2008) Dialkylphosphates (DAPs) in fruits and vegetables may confound biomonitoring in organophosphorus insecticide exposure and risk assessment. J Agric Food Chem. 2008 Nov 26;56(22):10638

- 45. doi: 10.1021/jf8018084.

RDI: RAB1 ( 9/15/15 )

cc: M.M. Perron

M.M. Perron : S1095 5 :PY

- S:(703) 347

- 0395 :7509P:RAB1

### Page 47 of 57 Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

Study requirements (40 CFR 158.340) for profenofos are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes
870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Nonrodents

............................. 870.3200 21/28

- Day Dermal Toxicity

................................ .......... 870.3250 90

- Day Dermal Toxicity

................................ ............... 870.3465 90

- Day Inhalation Toxicity

................................ ........... yes

yes

yes

no

yes yes

yes

yes

-- yes 870.3700a Prenatal Developmental Toxicity (rodent)

.................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

.............. 870.3800 Reproduction and Fertility Effects

................................ yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity/Carcinogenicity

............... yes

yes

yes

yes

yes yes 1

yes 2

yes 1

yes

yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

.......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes 870.6100 Acute Delayed Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neurotoxicity

................................ ....... yes

yes

yes

yes yes

yes

yes

yes
870.7485 Metabolism and Pharmacokinetics

................................ 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

-- yes

1 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.

2 Subchronic 90

- day and 6

- month studies are available; therefore, a longer term study is not required.

### Page 48 of 57 A.2. Toxicity Profiles

Table A.2.1. Acute Toxicity Profile for Technical Profenofos.

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (rat) 41714801 LD50 = Males: 492 (363

- 666) mg/kg Females: 809 (600

- 1090) mg/kg Combined: 630 mg/kg II

870.1100 Acute oral (mouse) 00105226 LD50 = 298 (268

- 332) mg/kg II

870.1100 Acute oral (rabbit) 00105228 LD50 = 300 mg/kg II

870.1200 Acute dermal (rat) 00105231 LD50 = 1610 (1073

- 2415) mg/kg II

870.1200 Acute dermal (rabbit) 00109427 LD50 = Intact skin

– Males: 146.8 mg/kg Females: 143.4 mg/kg

Abraded skin

- Males: 97.5 mg/kg Females: 15.9 mg/kg I

870.1300 Acute inhalation (rat) 00109428 LC50 = 3.36 mg/L IV

870.2400 Acute eye irritation (rabbit) 00109429 Minimal irritation, reversible within 7 days; no corneal opacity III

870.2500 Acute dermal irritation (rabbit) 41714802 Moderately irritating at 72 hours III

870.2600 Skin sensitization (guinea pig) 00109431 Sensitization was induced

-



### Note: Studies have not been updated to reflect current HED policy. Endpoint selection was driven by BMD modeling of the AChE activity to obtain BMD 10 

### and BMDL 10 

### values. As a result, updates to NOAEL/LOAEL values (or NOEL/LOEL values) in these studies would not ultimately impact current PODs or risk estimates. Consequently, the Agency did not find it necessary to update these studies at this time.

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

- Profenofos

. Guideline No. Study Type MRID No. /Doses Results

870.3100 90

- Day Oral Toxicity in Rodents (rat) 00105255 0, 0.2, 2, or 20 mg/kg/day NOEL = not established

. LOEL 0.2 mg/kg/day based on RBC, plasma and

brain AChE inhibition

.

870.3150 Subchronic Oral Toxicity in Non

Rodent (dog)

90 days 00108016 0, 0.05, 0.5, or 5 mg/kg/day Systemic NOEL = 5 mg/kg/day

. Systemic LOEL = not established.

Plasma AChE inhibition NOEL = not established

. Plasma AChE inhibition LOEL = 0.05 mg/kg/day

.

RBC AChE inhibition NOEL = 0.05 mg/kg/day

. RBC AChE inhibition LOEL = 0.5 mg/kg/day

.

Brain AChE inhibition NOEL = 0.5 mg/kg/day

. Brain AChE inhibition LOEL = 5 mg/kg/day

.

### Page 49 of 57 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

- Profenofos

. Guideline No. Study Type MRID No. /Doses Results

870.3150 Subchronic Oral Toxicity in Non

Rodent (dog)

6 months 00081687 0, 0.005, 0.05, 2.5, or 12.5 mg/kg/day NOEL = 0.005 mg/kg/day

. LOEL = 0.05 mg/kg/day based on AChE inhibition in plasma

.

870.3200 21

- Day Dermal Toxicity (rat) 41644501 0, 0.05, 1, or 10 mg/kg/d

Acceptable/guideline NOEL = 1 mg/kg/day

. LOEL = 10 mg/kg/day based on significant decreases in AChE in RBC, serum, and brain

.

870.3700a Prenatal Developmental in Rodent (rat) 00045031 0, 10, 30, or 60 mg/kg/day Maternal NOEL = 30 mg/kg/day

. Maternal LOEL = 60 mg/kg/day based on decreased food consumption and slightly decreased body weights

.

Developmental NOEL = 60 mg/kg/day

. Developmental LOEL = not established

.

870.3700b Prenatal Developmental in

Non

- Rodent (rabbit) 00128870 0, 30, 60, 90, or 175 mg/kg/day Maternal NOEL = 30 mg/kg/day

. Maternal LOEL = 60 mg/kg/day based on decreased body weight gain

.

Developmental NOEL = 175 mg/kg/day

. Developmental LOEL = not established

.

870.3800 Reproduction and Fertility Effects (rat) 43213308, 43213309 0, 0.36, 7.3, or 29 mg/kg/day Parental NOEL = 7.3 mg/kg/day

. Parental LOEL = 29 mg/kg/day based on decreased body weight, body weight gain, and food consumption

.

Offspring NOEL = 7.3 mg/kg/day

. Offspring LOEL = 29 mg/kg/day based on decreased pup body weight and body weight gain

.

Reproductive NOEL = 29 mg/kg/day

. Reproductive LOEL = not established

.

870.4100a Chronic Toxicity (rat) See 870.4300 See 870.4300

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity (mouse) 00082901 0, 0.15, 4.5 or 15 mg/kg/day NOEL = 0.15 mg/kg/day

. LOEL = 4.5 mg/kg/day based on AChE inhibition in plasma and RBC

.

No evidence of carcinogenicity

.

870.4300 Combined Chronic Toxicity/ Carcinogenicity (rat) 00081685 0, 0.015, 0.5, or 5 mg/kg/day NOEL = 0.015 mg/kg/day

. LOEL = 0.5 mg/kg/day based on AChE inhibition in RBC and plasma

.

No evidence of carcinogenicity

.

870.5100 Bacterial reverse

mutation 41866901 No increases in revertant colonies were observed in any strain up to 5000 μg/plate.

870.5375 In vitro mammalian cytogenetics 41945103 No aberrations reported up to cytotoxic levels (37.5 to 75 μg/mL)

.

870.5385 In vivo bone marrow cytogenetics (rat) 41945102 No induction of micronuclei up to a dose causing death (200 mg/kg)

.

870.555 0 Unscheduled DNA synthesis (UDS) in

mammalian cells 41945101 No increased grain count up to a dose producing 50% cytotoxicity (highest dose = 2.91 μg/mL)

.

### Page 50 of 57 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

- Profenofos

. Guideline No. Study Type MRID No. /Doses Results

870.6100 Acute Delayed Neurotoxicity (hen) 00126485 NOEL = 52 mg/kg

. 100% mortality at next highest dose of 104 mg/kg

LD 50 = 56.3 mg/kg

.

No delayed neurotoxicity

.

870.6200a Acute Neurotoxicity Screening Battery (rat) 42939801, 42939802 0, 95, 190, or 380 mg/kg NOEL = not established

. LOEL = 95 mg/kg based on AChE inhibition in plasma and RBC

.

870.6200b Subchronic Neurotoxicity Screening Battery (rat) 43213303, 43213304 0, 1.70/1.84, 7.7/8.4, or 36.0/37.9 mg/kg/day (M/F) Systemic NOEL = 7.7 mg/kg/day

. Systemic LOEL = 36 mg/kg/day based on slight decreases in body weight

.

Plasma and RBC AChE inhibition NOEL = not

established

. Plasma and RBC AChE inhibition NOEL = 1.7 mg/kg/day

.

Brain AChE inhibition NOEL = 7.7 mg/kg/day

. Brain AChE inhibition NOEL = 36 mg/kg/day

.

870.6300 Developmental Neurotoxicity (rat) 46025401, 46025402 0, 0.3, 5.1, or 50.6 mg/kg/day Maternal Systemic NOAEL = 5.1 mg/kg/d ay

. Maternal Systemic LOAEL = 50.6 mg/kg/day based on decreases in body weight, body weight gain, and food consumption

.

Maternal Cholinesterase NOAEL = 0.3 mg/kg/day

. Maternal Cholinesterase LOAEL = 5.1 mg/kg/day

based on AChE inhibition in RBC and brain

.

Offspring Systemic NOAEL = 5.1 mg/kg/day

. Offspring Systemic LOAEL = 50.6 mg/kg/day based on decreases in body weight, body weight gain, and food consumption

.

Offspring Cholinesterase NOAEL = 0.3 mg/kg/day

. Offspring Cholinesterase LOAEL = 5.1 mg/kg/day based on AChE inhibition in RBC, plasma, and

brain

.

### Page 51 of 57 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

- Profenofos

. Guideline No. Study Type MRID No. /Doses Results

870.7485 Metabolism and

Pharmacokinetics

Rat 42334301

- Single oral dose of 1 or 100 mg/kg of phenyl

- UL

- 14 C

- labeled profenofos

- Pre

- exposed to 1 mg/kg/day oral gavage of

non

- radiolabeled profenofos for 14 days before a single oral dose of 1 mg/kg 14 C

- profenofos R ecovery of radioactivity ranged from 97%

- 108%

of the administered dose for combined fecal and urine samples, with >97% of the radioactivity

excreted in the urine within 48 hours. Less than 0.2% of the radioactivity was expired as volatiles. Insignificant amounts were retained in any tissue after 7 days post

- exposure. Analysis of fecal

material indicated that <4% of the parent compound

or its metabolites are unabsorbed or excreted via the biliary system into the intestinal tract. Profenofos appears to be metabolized by hydrolysis of its thiophosphate ester followed by dephosphorylation

to form 4

- bromo

- 2

- chlorophenol (CG A

- 55960), which undergoes sulfate or glucuronide conjugation. Metabolites were identified as unconjugated 4

- bromo

- 2

- chlorophenol (CGA

55960), CGA

- 47196, and CGA

- 65867. There were no apparent dose or sex

- related differences in the absorption, distribution , metabolism, or excretion of profenofos.

870.7485 Metabolism and

Pharmacokinetics

Young adult male monkeys 46224401

single oral dose via capsule at 2.4 mg/animal (approximately 0.5 mg/kg) The test material was rapidly absorbed with significant concentrations measured in the blood and plasma by the first blood measurement (30 minutes post

- dose). T
max was reached by 1 hour
post

- dose and rapidly declined thereafter. The terminal phase elimination half

- life was estimated

to be 4 hours in this stud y. Approximately 68% of

the administered dose was recovered in the excreta (urine, feces, and cage wash after 168 hours) with the majority recovered in the urine (49%). Excretion was nearly complete by 24 hours following treatment. CGA

- 55163 was identif ied as the major urinary metabolite, which is the glucuronide conjugate of the phenol analog (CGA

55960).

870.7800 Immunotoxicity 48785801 0, 0.2, 6.4, or 67.6 mg/kg/day Systemic NOAEL = 67.6 mg/kg/day

. Systemic LOAEL = not established

.

Immunotoxicity NOAEL = 67.6 mg/kg/d ay

. Immunotoxicity LOAEL = not established

. Special Studies

Acute Comparative

Cholinesterase Study 46025405, 46025406 0, 1, 5, 25, or 100 mg/kg RBC AChE inhibition NOAEL = 1 mg/kg/day

. RBC AChE inhibition LOAEL = 5 mg/kg/day

.

Brain AChE inhibition NOAEL = 5 mg/kg/day

. Brain AChE inhibition LOAEL = 25 mg/kg/day

. Repeated Comparative

Cholinesterase Study 46025403, 46025404 0, 0.5, 5, or 50 mg/kg/day RBC AChE inhibition NOAEL = not established

. RBC AChE inhibition LOAEL = 0.5 mg/kg/day

.

Brain AChE inhibition NOAEL = not established

. Brain AChE inhibition LOAEL = 0.5 mg/kg/day

.

### Page 52 of 57 Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling

OPP’s ChE policy (USEPA, 2000 16 

### ) describes the manner in which ChE data are used in human health risk assessment. The following text provides a brief summary of that document to provide context to points of departure selected.

AChE inhibition can be inhibited in the central or perip heral nervous tissue. Measurements of AChE or ChE inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung

, etc.) are rare. As such, experimental laboratory studies generally measure brain (central) and blood (plasma and red blood cell, RBC) ChE. Blood measures do not represent the target tissue, per se , but are instead used as surrogate measures for peripheral toxicity in studies with laboratory animals or for peripheral and/or central toxicity in humans. In addition, RBC measures represent AChE, whereas plasma measures are predominately butyryl

- ChE (BuChE). Thus, RBC AChE data may provide a better representation of the inhibition in target tissues. As part of the dose response assessment, evaluations of neurobehavior and clinical signs are performed to consider the dose response linkage between AChE inhibition and apical outcomes.

Refinements to OPP’s use of ChE data have come in the implementation of BMD approaches in dose response assessment. Beginning with the OP CRA, OPP has increased its use of BMD modeling to derive PODs for AChE inhibiting compounds. Most often the decreasing exponential empirical model has been used.

OPP does have not a defined BMR for OPs. However, the 10% level has been used in the majority of dose response analyses conducted to date. This 10% level represents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls). Specifically, the BMD 10 

### is the estimated dose where ChE is inhibited by 10% compared to backg round. The BMDL 10 

### is the lower confidence bound on the BMD 10



### .

The use of the 10% BMR is derived from a combination of statistical and biological considerations. A power analysis was conducted by ORD on over 100 brain AChE datasets

across more than 25 OPs as part of the OP CRA (USEPA, 2002). This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In addition, the 10% level is generally at or near the limit of sensitivity for discerning a st atistically significant decrease in ChE activity in the brain compartment and is a response level close to the background brain ChE level. With respect to biological considerations, a change in 10% brain AChE inhibition is protective for downstream clinic al signs and apical neurotoxic outcomes. With respect to RBC AChE inhibition, these data tend to be more variable than brain AChE data. OPP begins its BMD analyses using the 10% BMR for RBC AChE inhibition but BMRs up to

20% could be considered on a case

- by

- case basis as long as such PODs are protective for brain AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.

16 USEPA (2000) Office of Pesticide Programs, US Environmental Protection Agency, Washington DC 20460. August 18, 2000 Office of Pesticide Programs Science Policy of The Use of Data on Cholinesterase Inhibition

for Risk Assessments of Organophosphorous and Carbamate Pesticides.

### Page 53 of 57 Appendix C. Summary Tables of Benchmark Dose (BMD) Analyses

Toxicity studies with AChE data were analyz ed using the most recent version of EPA’s Benchmark Dose Software (Version 2.4). In Tables C.1

- C.3, results have been summarized. Full results and technical details for these analyses can be found in the latest BMD analysis

memo (M. Perron; 15

- SEP

- 2015 ; TXR # 0057250 ).

Table C.1. Summary of BMD Results Following Acute Exposures to Profenofos. 1

Study Age Compartment Males Females

BMD 10 (mg/kg/day) BMDL 10 (mg/kg/day) BMD 10 (mg/kg/day) BMDL 10 (mg/kg/day)

Rat Acute Comparative

Cholinesterase Assay

- Gavage (MRID 46025406) D12 RBC NMF NMF 13.68 9.31

Brain 9.57 7.75 10.29 7.16

D22 RBC 7.43 4.60 14.99 12.06

Brain 20.2 14.4 31.12 14.92

D42 RBC 13.49 11.24 3.17 1.99

Brain NMF NMF NMF NMF

Rat Acute Non

Guideline Oral Study

- Gavage (MRID 43213302) Adult RBC 26.1 3.46 8.78 4.45

BMD 10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL 10 = lower 95%

confidence interval for BMD 10 . N MF = no statistical or visual model fit. D = day.

1 T he acute neurotoxicity study is not shown

. The data were not found to be amenable to BMD modeling because rats were dosed too high (95

- 380 mg/kg) causing extrapolation to much lower doses to obtain BMD 10 estimates.

Table C.2. Summary of BMD Results Following Repeated Exposures to P rofenofos.

Study Age Compartment Males Females

BMD 10 (mg/kg/day) BMDL 10 (mg/kg/day) BMD 10 (mg/kg/day) BMDL 10 (mg/kg/day)

Rat Studies

Rat Repeat Comparative Cholinesterase Assay

- Gavage (MRID 46025403) D12 post

- partum RBC 0.69 0.51 0.49 0.24

Brain NMF NMF 6.26 5.81

D42 post

- partum RBC NMF NMF 0.38 0.17

Brain NMF NMF 18.18 7.22

Rat Developmental Neurotoxicity Study

– Dietary (MRID 46025401) Fetus (GD22) RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D5 post

- partum RBC NDR NDR NDR NDR

Brain NDR NDR 37.09 16.16

D12 post

- partum RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D22 post

- partum RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

Pregnant Dams (GD22) RBC

- - 0.51 0.37

Brain

- - 46.31 7.63

Non

- pregnant females

(D22 post

- partum ) RBC

- - 0.32 0.19

Brain

- - 42.57 5.19

Fetus (GD22) RBC NDR NDR 22.38 12.31

### Page 54 of 57 Range

- Finding Rat Developmental Neurotoxicity Study

– Dietary (MRID 46025402) Brain NDR NDR NDR NDR

D5 post

- partum RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D12 post

- partum RBC NDR NDR 94.6 40.5

Brain NDR NDR NDR NDR

D22 post

- partum RBC 15.51 12.34 NMF NMF

Brain 42.81 20.41 43.65 27.96

Pregnant Dams (GD22) RBC

- - 1.78 1.09

Brain

- - NDR NDR

Non

- pregnant females

(D22 post

- partum ) RBC

- - 0.53 0.31

Brain

- - 13.7 7.99

Subchronic Oral Rat

– Dietary (MRID 00105255) Adult RBC 0.33 0.29 0.66 0.54

Rat Subchronic Neurotoxicity Study

– Dietary (MRID 43213303) Adult RBC 0.12 a 0.05 a 0.23 a 0.19 a

13 Week Interim

Measurement in Rat Chronic/Carcinogenicity Study

– Dietary (MRID 00081685) Adult RBC 0.14 0.12 0.13 0.12

Terminal Measurement

in Rat Chronic/Carcinogenicity Study

– Dietary (MRID 00081685) Adult RBC 0.17 0.15 0.22 0.18

Dog Studies Subchronic Oral Dog

– Dietary (MRID 00108016 Adult RBC NMF b NMF b NMF b NMF b

Mouse Studies Mouse Carcinogenicity Study

– Dietary (MRID 00081686) Adult RBC 0.21 a 0.08 a 0.78 a 0.57 a

a Poor dose spacing forced extrapolation to a much lower value to obtain BMD 10 and BMDL 10 values.

b Large variability noted at all doses and ground truthing found no AChE inhibition in the raw data for the BMD 10 values generated.

BMD 10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL 10 = lower 95%

confidence interval for BMD 10

. NMF = no statistical or visual model fit. NDR = no dose response. D = day.

### Page 55 of 57 Table C. 3 . Summary of BMD Results for Route

- Specific Studies.

Study Age Compartment Males Females

BMD 10 BMDL 10 BMD 10 BMDL 10

Rabbit Dermal Toxicity Study (MRID 41644501) Adult RBC NMF a NMF a NMF a NMF a

Rat Inhalation Toxicity Study (MRID 00082079) Adult RBC NMF b NMF b NMF b NMF b

a Flat dose response with a decrease only at the highest dose tested and relatively large variability noted at all doses.

b Mortality at the highest dose tested left only 2 treatment groups for modeling and poor dose selection forced extrapolation to a much lower value from the lowest dose to obtain a BMD 10 and BMDL 10 values.

BMD 10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL 10 = lower 95%

confidence interval for BMD 10 . NMF = no statistical or visual model fit.

### Page 56 of 57 Appendix D . Physical/Chemical Properties

Table D.1. Physicochemical Properties of Technical Grade Profenofos.

Parameter Value Reference Melting Point/Range N/A MRID 42030301, 42854201 pH 3

- 5 Specific Gravity 1.46 g/cm 3 at 20oC Solvent Solubility (at 25oC) Completely miscible in ethanol, acetone, toluene,

n

- octanol, and n

- hexane

Vapor Pressure (20oC) 9.001 x 10

- 7 mm Hg Dissociation Constant (pK
a ) N/A Octanol/Water Partition Coefficient (Log[K OW ]) 4.83

### Page 57 of 57 Appendix E

. International Residue Limits

Table E.1. Summary of US and International Tolerances and Maximum Residue Limits (MRLs) for

Profenofos.

Commodity Tolerances or MRLs (ppm)

US Canada Mexico 1 Codex 2

Residue Definition:

40CFR180.404 profenofos (O

- (4

- bromo

- 2

- chlorophenyl)

- O

- ethyl

- S

- propyl phosphorothioate) None Profenofos

Cattle, fat 0.05

Cattle, meat 0.05 0.05 (*) meat (from mammals other than marine mammals)

Cattle, meat byproducts 0.05 0.05 (*) edible offal (mammalian) Cotton, gin byproducts 55.0
Cotton, undelinted seed 2.0 3 cotton seed
Goat, fat 0.05

Goat, meat 0.05 0.05 (*) meat (from mammals other than marine mammals)

Goat, meat byproducts 0.05 0.05 (*) edible offal (mammalian)
Horse, fat 0.05

Horse, meat 0.05 0.05 (*) meat (from mammals other than marine mammals)

Horse, meat byproducts 0.05 0.05 (*) edible offal (mammalian)

Milk 0.01 0.01 (*) Sheep, fat 0.05

Sheep, meat 0.05 0.05 (*) meat (from mammals other than marine mammals)

Sheep, meat byproducts 0.05 0.05 (*) edible offal (mammalian) MRLs with NO US Equivalent Eggs 0.02 (*) Mango 0.2 Mangostan 10

Peppers, chili 3 20 peppers Chili, dried Poultry meat 0.05 (*) Poultry, edible offal of 0.05 (*) Spices, fruits, and berries 0.07 Spices, roots and rhizomes 0.05 Teas (tea and herb teas) 0.5

Tomato 10 Completed by: M. Negussie; 04/09/15

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.